Clinical Trial Results:
Ibuprofen versus mecillinam for uncomplicated cystitis in adult, non-pregnant women
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Summary
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EudraCT number |
2012-002776-14 |
Trial protocol |
NO DK SE |
Global end of trial date |
07 Jun 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Jun 2021
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First version publication date |
10 Jun 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
97
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01849926 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Oslo
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Sponsor organisation address |
Postboks 1130, Blindern, Oslo, Norway, 0318
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Public contact |
Ingvild Vik, University of Oslo, 0047 23487000, ingvild.vik@medisin.uio.no
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Scientific contact |
Ingvild Vik, University of Oslo, 0047 23487000, ingvild.vik@medisin.uio.no
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Jun 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Jun 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Jun 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Although uncomplicated cystitis is considered to be a mild condition and mostly self limiting, most patients who see a doctor will be treated with antibiotics. Antibiotics are known to give a quick relief of symptoms and shorten the course of the condition by a few days.
The aim of this study is to evaluate ibuprofen versus mecillinam in the treatment of uncomplicated cystitis in otherwise healthy, non-pregnant women.
Our main objective is to see whether symptomatic treatment with ibuprofen is equally efficiant as treatment with mecillinam in this group.
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Protection of trial subjects |
The patients received information about the trial, intervention and follow-up at inclusion by a doctor or a study nurse. All study personnel were trained in GCP. The patients received contact information to the study site and to the study doctor and were welcome to contact the study site or the study doctor at any time throughout the trial if they had any questions or concerns.
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Background therapy |
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Evidence for comparator |
We chose to use an NSAID instead of paracetamol because of its greater anti-inflammatory effect, presumably providing better pain relief. We chose to use ibuprofen over other NSAIDs because of its relatively beneficial adverse effect profile. We decided to use a relatively high dosage, 600 mg three times a day, in order to achieve the best possible pain relief. The dosage is well within the maximum recommended daily intake (2400 mg). We chose pivmecillinam because it is a narrow spectrum antibiotic and a first line treatment option for uUTIs in Scandinavia. It has selective activity against Gram-negative bacteria, especially E. coli, a relatively low resistance-driving effect and beneficial adverse effect profile. In Norway and Sweden, the guidelines recommend 200 mg of pivmecillinam three times a day for three days as standard empirical treatment for uUTIs. In Denmark, however, they recommend 400 mg three times a day for three days. Both regimens have proven effectiveness, and since two out of three countries recommend the lower dosage we agreed upon using that regimen in the trial. The study was designed to establish the non-inferiority of ibuprofen compared to pivmecillinam treatment regarding symptomatic relief four days after treatment initiation by a 10% inferiority margin. There is ample evidence that immediate antibiotics are superior to placebo in the treatment of uUTIs. The non-inferiority design was chosen because we wanted to test whether ibuprofen was a good enough treatment for uUTIs with regards to symptomatic relief, compared to the established treatment regimen. The trial was designed and conducted according to the CONSORT criteria with relevant extensions for non-inferiority trials. | ||
Actual start date of recruitment |
11 Apr 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Norway: 300
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Country: Number of subjects enrolled |
Sweden: 37
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Country: Number of subjects enrolled |
Denmark: 46
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Worldwide total number of subjects |
383
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EEA total number of subjects |
383
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
383
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were assessed for eligibility from 11 April 2013 to 22 April 2016, and the last follow-up was made on 7 June 2016. The largest recruitment site was the AEOC in Oslo (260 patients), followed by the AEOC in Bergen (40 patients). In Denmark study personnel recruited 47 patients, and in Sweden they recruited 37 patients. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
We recruited non-pregnant women aged 18–60 years with symptoms of an uncomplicated UTI. Inclusion criteria were dysuria combined with either increased urinary frequency or urinary urgency or both. 2,942 women were screened: 1,290 patients met 1 or more exclusion criteria, 1,269 patients were eligible, and 383 patients were enrolled in the trial. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer | ||||||||||||||||||||||||||||||
Blinding implementation details |
The study medicine was over-encapsulated. They used gelatin capsules where red iron oxide was used for color and titanium oxide as an opacifier. The study medicine was packed in 2 different kits, one with 9 capsules containing 200 mg pivmecillinam each, the other with 9 capsules containing 600 mg ibuprofen each .Each kit was labeled with a study number following a computer-generated randomization list created by an independent statistician using randomized block sizes of 2, 4, 6, or 8.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pivmecillinam | ||||||||||||||||||||||||||||||
Arm description |
Pivmecillinam, 200 mg x3 for three days. | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pivmecillinam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
200mg x3 for three days.
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Arm title
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Ibuprofen | ||||||||||||||||||||||||||||||
Arm description |
Ibuprofen 600mg x3 for three days | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ibuprofen
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Ibuprofen 600 mg x3 for three days
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Pivmecillinam
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Reporting group description |
Pivmecillinam, 200 mg x3 for three days. | ||
Reporting group title |
Ibuprofen
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Reporting group description |
Ibuprofen 600mg x3 for three days | ||
Subject analysis set title |
Full analysis set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The primary efficacy analyses were performed in the FAS, consisting of all randomized patients with at least 1 efficacy assessment after randomization. There were no missing data for the primary endpoint in the FAS.
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End point title |
The proportion of patients who felt cured by day 4 | ||||||||||||||||
End point description |
The main outcome measure of this trial was the proportion of patients who felt cured by day 4 as recorded in the patient diary. If we did not have information from the diary, we used the number of days until cure reported by the patient during the telephone follow-up.
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End point type |
Primary
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End point timeframe |
4 days
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Statistical analysis title |
Non-inferiority, logistic regression | ||||||||||||||||
Statistical analysis description |
Assuming no difference between the treatment groups in the proportion of patients feeling cured after 4 days, we calculated that 316 patients were required in the primary full analysis set (FAS) analyses to be 80% confident that the 1-sided 95% confidence limit would exclude a difference in favor of pivmecillinam of more than 10%. The primary and secondary dichotomous endpoints were analyzed using logistic regression or mixed effects logistic regression with treatment as a fixed effect.
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Comparison groups |
Pivmecillinam v Ibuprofen
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Number of subjects included in analysis |
359
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||
P-value |
> 0.99 [2] | ||||||||||||||||
Method |
Regression, Linear | ||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||
Point estimate |
35
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Confidence interval |
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level |
90% | ||||||||||||||||
sides |
2-sided
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lower limit |
27 | ||||||||||||||||
upper limit |
43 | ||||||||||||||||
| Notes [1] - The null hypothesis of this study was that treatment with ibuprofen would be inferior to pivmecillinam regarding the proportion of patients feeling cured after 4 days by a 10% margin. The alternative hypothesis was that ibuprofen would be non-inferior regarding the proportion of patients feeling cured after 4 days by at most 10%. [2] - In the ibuprofen group, 70 patients (38.7%) felt cured by day 4 versus 131 patients (73.6%) in the pivmecillinam group (Table 2). Adjusted risk difference with 90% CI was 35% (27% to 43%), which is outside the predefined non-inferiority margin. |
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Adverse events information
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Timeframe for reporting adverse events |
4 weeks/28 days
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Adverse event reporting additional description |
All adverse events were registered in the patient diary and reported. Serious adverse events were recorded and reported to the authorities according to GCP.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
ICD-10 | |||||||||||||||||||||||||||||||||
Dictionary version |
2017
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Reporting groups
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Reporting group title |
Pivmecillinam
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Reporting group description |
Patients who received treatment with pivmecillinam | |||||||||||||||||||||||||||||||||
Reporting group title |
Ibuprofen
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Reporting group description |
Patients who received treatment with ibuprofen | |||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| A weakness was the extensive list of exclusion criteria, eliminating almost half of the patients presenting with symptoms of an uncomplicated UTI. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/29763434 |
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