Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   43977   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Ibuprofen versus mecillinam for uncomplicated cystitis in adult, non-pregnant women

    Summary
    EudraCT number
    2012-002776-14
    Trial protocol
    NO   DK   SE  
    Global end of trial date
    07 Jun 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Jun 2021
    First version publication date
    10 Jun 2021
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    97
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01849926
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oslo
    Sponsor organisation address
    Postboks 1130, Blindern, Oslo, Norway, 0318
    Public contact
    Ingvild Vik, University of Oslo, 0047 23487000, ingvild.vik@medisin.uio.no
    Scientific contact
    Ingvild Vik, University of Oslo, 0047 23487000, ingvild.vik@medisin.uio.no
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    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.
    Background therapy
    -
    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
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 300
    Country: Number of subjects enrolled
    Sweden: 37
    Country: Number of subjects enrolled
    Denmark: 46
    Worldwide total number of subjects
    383
    EEA total number of subjects
    383
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    383
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    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.

    Pre-assignment
    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.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    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.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pivmecillinam
    Arm description
    Pivmecillinam, 200 mg x3 for three days.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pivmecillinam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    200mg x3 for three days.

    Arm title
    Ibuprofen
    Arm description
    Ibuprofen 600mg x3 for three days
    Arm type
    Active comparator

    Investigational medicinal product name
    Ibuprofen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibuprofen 600 mg x3 for three days

    Number of subjects in period 1
    Pivmecillinam Ibuprofen
    Started
    189
    194
    Completed
    154
    150
    Not completed
    35
    44
         Adverse event, non-fatal
    2
    -
         Drop outs (no post baseline information
    -
    13
         Drop outs
    11
    -
         Lost to follow-up
    17
    19
         Felt well
    5
    4
         Lack of efficacy
    -
    8

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    383 383
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Women, 18-60 years.
    Units: years
        median (standard deviation)
    25 ± 8 -
    Gender categorical
    Women only
    Units: Subjects
        Female
    383 383
        Male
    0 0

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Pivmecillinam
    Reporting group description
    Pivmecillinam, 200 mg x3 for three days.

    Reporting group title
    Ibuprofen
    Reporting group description
    Ibuprofen 600mg x3 for three days

    Subject analysis set title
    Full analysis set
    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.

    Primary: The proportion of patients who felt cured by day 4

    Close Top of page
    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.
    End point type
    Primary
    End point timeframe
    4 days
    End point values
    Pivmecillinam Ibuprofen Full analysis set
    Number of subjects analysed
    178
    181
    359
    Units: 73.6%
        number (not applicable)
    131
    70
    201
    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.
    Comparison groups
    Pivmecillinam v Ibuprofen
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    > 0.99 [2]
    Method
    Regression, Linear
    Parameter type
    Risk difference (RD)
    Point estimate
    35
    Confidence interval
         level
    90%
         sides
    2-sided
         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.

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    4 weeks/28 days
    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.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    ICD-10
    Dictionary version
    2017
    Reporting groups
    Reporting group title
    Pivmecillinam
    Reporting group description
    Patients who received treatment with pivmecillinam

    Reporting group title
    Ibuprofen
    Reporting group description
    Patients who received treatment with ibuprofen

    Serious adverse events
    Pivmecillinam Ibuprofen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 189 (0.53%)
    6 / 181 (3.31%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Pyelonephritis
    Additional description: Serious adverse events were defined as any event leading to hospitalization. In the pivmecillinam group there was one hospitalization not related to the study, in the ibuprofen group 5 hospitalizations were related to the study, 1 unclear.
         subjects affected / exposed
    1 / 189 (0.53%)
    6 / 181 (3.31%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Pivmecillinam Ibuprofen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 189 (20.11%)
    32 / 181 (17.68%)
    General disorders and administration site conditions
    Various symptoms and signs
    Additional description: I have reported the total number of non serious adverse events, they are listed in detail in table 4 in the result article in PLOS Medicine.
         subjects affected / exposed
    38 / 189 (20.11%)
    32 / 181 (17.68%)
         occurrences all number
    49
    40

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    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

    http://www.ncbi.nlm.nih.gov/pubmed/29763434
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA