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    Clinical Trial Results:
    Efficacy of propiverine hydrochloride extended release (ER) 45 mg in patients with neurogenic detrusor overactivity – an active-controlled single center crossover trial

    Summary
    EudraCT number
    		 2012-003159-12
    Trial protocol
    		 DE  
    Global end of trial date
    16 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2023
    First version publication date
    09 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8405011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    APOGEPHA Arzneimittel GmbH
    Sponsor organisation address
    Kyffhäuserstr. 27, Dresden, Germany, 01309
    Public contact
    Clinical Development Department, APOGEPHA Arzneimittel GmbH, +49 35133633, Studien@apogepha.de
    Scientific contact
    Clinical Development Department, APOGEPHA Arzneimittel GmbH, +49 35133633, Studien@apogepha.de
    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
    16 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the efficacy of propiverine hydrochloride ER 45 mg s.i.d. versus propiverine hydrochloride IR 15 mg t.i.d. in patients with NDO in terms of percent change of bladder volume at first detrusor contraction in relation to the baseline value measured after the run-in phase.
    Protection of trial subjects
    Safety was evaluated by collecting reported adverse events (AEs) at regular intervals throughout the study and by the assessment of physical examination findings, vital signs, clinical laboratory parameters, and ECGs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 2012
    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
    Germany: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    17
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients were recruited from the ambulatory study center patient pool or from patients who had been treated acutely in the clinic (BDH Klinik Greifswald, Neurologisches Rehabilitationszentrum und Querschnittgelähmtenzentrum, Germany) after the neurologic status had been stabilized.

    Pre-assignment
    Screening details
    		 - Female and male patients aged 18 years or older with NDO due to spinal cord injuries. - Primarily proven NDO with evidence of reflex detrusor contractions in previous pressure-flow-studies. - Ability to practice clean intermittent catheterization (by the patient himself or a nurse/relative) at least 4 to 6 times daily.

    Period 1
    Period 1 title
    Treatment A
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Arm title
    		 Treatment A
    Arm description
    		 Treatment A: Mictonorm Uno® 45 mg, 1 capsule (45 mg propiverine hydrochloride ER) s.i.d. and one tablet of placebo matching Mictonorm ®.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mictonorm Uno 45 mg
    Investigational medicinal product code
    84546.00.00
    Other name
    Propiverine ER
    Pharmaceutical forms
    Modified-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Each patient had to take 1 capsule of Mictonorm Uno® 45 mg and 1 tablet of placebo matching Mictonorm® in the morning, 1 tablet at noon and 1 tablet in the evening at approximately 8 h intervals.

    Number of subjects in period 1
    		Treatment A
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Treatment B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Arm title
    		 Treatment B
    Arm description
    		 Treatment B: Mictonorm® coated tablets (15 mg propiverine hydrochloride IR) t.i.d. and one capsule of placebo matching Mictonorm Uno® 45 mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Mictonorm®
    Investigational medicinal product code
    3000574.00.00
    Other name
    Mictonorm 15 mg, Propiverine IR
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each patient had to take 1 capsule of placebo matching Mictonorm Uno® 45 mg and 1 tablet of Mictonorm® in the morning, 1 tablet at noon and 1 tablet in the evening at approximately 8 h intervals.

    Number of subjects in period 2
    		Treatment B
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 -

    Reporting group values
    		 Treatment A Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        Patients aged 18 years or older
    		 20 20
    Age continuous
    Units: years
        median (standard deviation)
    		 45.5 ( 14.7 ) -
    Gender categorical
    18 patients were males and 2 females.
    Units: Subjects
        Female
    		 2 2
        Male
    		 18 18

    End points

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    End points reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Treatment A: Mictonorm Uno® 45 mg, 1 capsule (45 mg propiverine hydrochloride ER) s.i.d. and one tablet of placebo matching Mictonorm ®.
    Reporting group title
    Treatment B
    Reporting group description
    		 Treatment B: Mictonorm® coated tablets (15 mg propiverine hydrochloride IR) t.i.d. and one capsule of placebo matching Mictonorm Uno® 45 mg

    Subject analysis set title
    IIT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All 20 subjects received double-blind medication according to protocol. Per-protocol and ITT population consisted of these 20 patients and were identical.

    Primary: Reflex volume

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    End point title
    		 Reflex volume
    End point description
    The reflex volume, defined as volume at "starting of first hyperactive detrusor contraction", has been chosen as primary efficacy outcome since it reflects the main treatment aims in patients with NDO: reduction of intravesical pressure in order to minimize or even eliminate complications of the upper urinary tract and increase of maximum bladder capacity with reduction of incontinence episodes or achievement of continence. If no RV occurred during the cystometric measurement, RV was equated to the maximum bladder capacity, in this case to the predefined filling volume of 450 mL.
    End point type
    Primary
    End point timeframe
    Cystometric measurements were performed three times: after the run-in period, but before randomization into the two treatment periods, and after each treatment period of at least 21 days duration. Each patient received cross-over treatment.
    End point values
    		 Treatment B Treatment A
    Number of subjects analysed
    20
    20
    Units: millilitre(s)
        median (standard deviation)
    320 ( 149 )
    340 ( 135 )
    Statistical analysis title
    		 GEE proportional odds model
    Statistical analysis description
    Generalized estimating Equations (GEE), an extension of generalized linear models, using logit or cumulative logits as link function. Anticipated statistical method if more than 25% of the urodynamic parameters were censored. Effects considered were treatment, seqeunce and study period. It must be considered that the so-called baseline was determined under active treatment with propiverine IR (Mictonorm ® 15 mg t.i.d.), which was identical to the reference treatment (propiverine IR). T
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.1575
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4594
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1563
         upper limit
    		 1.3509
    Notes
    [1] - The primary variable RV with values >450 ml was censored in 35% of cases after all treatments. Thus, the preconditions for evaluation according to a mixed effect model were not given. For such a case, the statistical analysis plan foresaw an evaluation by means of a three level score using a GEE proportional odds dole. The levels were: <200 ml, inadequate effect; 200 - 400 ml, acceptable effect, >400 ml, good effect.

    Secondary: Maximum cystometric capacity

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    End point title
    		 Maximum cystometric capacity
    End point description
    End point type
    Secondary
    End point timeframe
    Cystometric measurements were performed three times: after the run-in period, but before randomization into the two treatment periods, and after each treatment period of at least 21 days duration. Each patient received cross-over treatment.
    End point values
    		 Treatment B Treatment A
    Number of subjects analysed
    20
    20
    Units: ml
        median (standard deviation)
    450 ( 98.9 )
    450 ( 88.8 )
    Statistical analysis title
    		 GEE proportional odds model MCC
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3335
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7849
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4805
         upper limit
    		 1.2823

    Secondary: Detrusor pressure

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    End point title
    		 Detrusor pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Cystometric measurements were performed three times: after the run-in period, but before randomization into the two treatment periods, and after each treatment period of at least 21 days duration. Each patient received cross-over treatment.
    End point values
    		 Treatment B Treatment A
    Number of subjects analysed
    20
    20
    Units: cm H20
        median (standard deviation)
    6 ( 23 )
    6.5 ( 18.8 )
    Statistical analysis title
    		 GEE proportional odds model Pdet
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6774
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.2273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4677
         upper limit
    		 3.2203

    Secondary: Maximum detrusor pressure

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    End point title
    		 Maximum detrusor pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Cystometric measurements were performed three times: after the run-in period, but before randomization into the two treatment periods, and after each treatment period of at least 21 days duration. Each patient received cross-over treatment.
    End point values
    		 Treatment B Treatment A
    Number of subjects analysed
    20
    20
    Units: cm H20
        median (standard deviation)
    12 ( 28.7 )
    11.5 ( 27.5 )
    Statistical analysis title
    		 GEE proportional odds model Pdet max
    Comparison groups
    Treatment B v Treatment A
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9898
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.0042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5249
         upper limit
    		 1.9215

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    at visit 2 for run-in phase, at visit 3 for treatment periode 1 and at visit 4 for treatment periode 2.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Treamtent A - Propiverine ER
    Reporting group description
    		 All randomised patient treated with Treatment A

    Reporting group title
    Treatment B - Propiverine IR
    Reporting group description
    		 All randomised patient treated with Treatment B

    Serious adverse events
    		 Treamtent A - Propiverine ER Treatment B - Propiverine IR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treamtent A - Propiverine ER Treatment B - Propiverine IR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 20 (30.00%)
    4 / 20 (20.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Bacteriuria
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2013
    Adaption of inclusion criteria, agreed by investigator
    09 Jul 2013
    Brief description of change: The term “laboratory” was deleted in section 4.4. In the routine way of clinical work, the laboratory samples will be sent for evaluation to the laboratory. The samples are no pseudonymised because the results will be used for further treatment of the patients. The results will be stored in the ambulatory medical patient file and will not be passed on to the Sponsor or any other third parties.

    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.
    None reported
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