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    Clinical Trial Results:
    Exploratory, randomized, double-blind, placebo-controlled evaluation of efficacy, tolerability, and safety of intravesical instillation of GRT6010 compared to placebo in subjects with bladder pain syndrome

    Summary
    EudraCT number
    2016-003940-35
    Trial protocol
    DE   PL  
    Global end of trial date
    02 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Feb 2019
    First version publication date
    14 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF6010-02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1188-0214
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52078
    Public contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com
    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
    11 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy of intravesical instillation of GRT6010 on pain.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local law and regulations, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory authorities were notified of the trial as required by national regulations, necessary relevant authorization was obtained. Furthermore, the competent authorities were notified of this trial in accordance with national requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jul 2017
    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
    Poland: 71
    Country: Number of subjects enrolled
    Germany: 6
    Worldwide total number of subjects
    77
    EEA total number of subjects
    77
    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)
    67
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First subject signed informed consent on the 26 July 2017 and the last subject completed the trial on the 02 May 2018.

    Pre-assignment
    Screening details
    A total of 77 subjects signed an informed consent. 57 of these subjects were allocated to treatment (25 Placebo, 32 GRT6010). 2 placebo subjects and 1 GRT6010 subject never received IMP.

    Pre-assignment period milestones
    Number of subjects started
    77
    Number of subjects completed
    54

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 5
    Reason: Number of subjects
    Inclusion criteria not met/exclusion criteria met: 14
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    No IMP administration: 3
    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, Assessor
    Blinding implementation details
    This trial used double blind methods to guarantee the blinding of all personnel involved in the trial. Subjects and investigators were blinded to the subjects’ treatments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GRT6010
    Arm description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of GRT6010 solution.
    Arm type
    Experimental

    Investigational medicinal product name
    GRT6010 solution for instillation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    10 ml of a GRT6010 solution (30 μg/mL) were instilled in the bladder at each of the 4 Treatment Visits via single use bladder catheters.

    Arm title
    Placebo
    Arm description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of matching placebo solution.
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo solution for instillation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    10 ml of a placebo solution were instilled in the bladder at each of the 4 Treatment Visits via single use bladder catheters.

    Number of subjects in period 1 [1]
    GRT6010 Placebo
    Started
    31
    23
    Completed
    31
    23
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 77 subjects signed an informed consent. 54 subjects received at least one dose of investigational medicinal product.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GRT6010
    Reporting group description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of GRT6010 solution.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of matching placebo solution.

    Reporting group values
    GRT6010 Placebo Total
    Number of subjects
    31 23 54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    26 21 47
        From 65-84 years
    5 2 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.2 ± 15 42.9 ± 16.3 -
    Gender categorical
    Units: Subjects
        Female
    31 23 54
        Male
    0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Black or African American
    0 0 0
        Native Hawaiian or other Pacific Islander
    0 0 0
        White
    31 23 54
        Other
    0 0 0
        Not reported
    0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0 0
        Not Hispanic or Latino
    31 23 54
        Unknown
    0 0 0
        Not reported
    0 0 0
    Height
    Units: meter
        arithmetic mean (standard deviation)
    1.632 ± 0.064 1.643 ± 0.064 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    68.16 ± 13.64 64.10 ± 9.60 -
    Body Mass Index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    25.64 ± 5.25 23.82 ± 3.92 -
    Baseline pain intensity
    The baseline daily pain score was calculated as the pain intensity averaged over the last 3 days prior to first IMP. Subjects were documenting pain intensity scores using an e-diary. Pain scores were obtained twice daily (morning and evening). Subjects were asked: “Please indicate how much bladder pain you had on average since the last assessment”. The visual analog scale (VAS) 0-100 were labeled with 0 = "no pain” and 100 = "pain as bad as you can imagine”. At least 4 out of 6 ratings and at least 1 rating per day were required for an evaluable baseline assessment.
    Units: units on a scale
        arithmetic mean (standard deviation)
    76.8 ± 10.6 79.6 ± 10.9 -
    Baseline micturition frequency
    Average number of daily micturition at baseline was calculated as the number of micturitions averaged over the last 3 days prior to Treatment Visit 1.
    Units: frequency
        arithmetic mean (standard deviation)
    12.3 ± 4.1 12.5 ± 4.6 -
    Baseline urine volume per voiding
    Average daily urine volume per voiding at baseline was calculated as the volume per voiding over the last 3 days prior to Treatment Visit 1.
    Units: milliliter(s)
        arithmetic mean (standard deviation)
    140.0 ± 72.7 147.4 ± 84.4 -
    Baseline intensity of urgency
    Intensity of urgency was assessed on a 0–100 VAS twice daily (morning and evening). Average daily intensity of urgency at baseline was calculated as the intensity of urgency averaged over the last 3 days prior to Treatment Visit 1. Subjects were asked: “Please indicate the intensity of your micturition urgency on average since the last assessment”. The VAS was labeled with 0 = "no urgency” and 100 = "urgency as bad as you can imagine”.
    Units: units on a scale
        arithmetic mean (standard deviation)
    74.3 ± 14.5 79.0 ± 11.5 -
    Baseline O’Leary/Sant questionnaire scores - Symptom Index
    The O’Leary/Sant questionnaire consists of 2 brief, self-administered indices for measuring lower urinary tract symptoms and their impact in patients with bladder pain syndrome (BPS). It assesses severity of symptoms and how much of a problem the symptoms cause for the patient. Symptom and problem index scores are scored from 0 to 20 (0 = no symptoms/problems, 20 = worst symptoms/problems). The symptom index is able to discriminate characteristics between patients and controls (O’Leary et al. 1997). A 1 month recall period was used.
    Units: units on a scale
        arithmetic mean (standard deviation)
    15.4 ± 2.8 14.5 ± 2.4 -
    Baseline O’Leary/Sant questionnaire scores - Problem Index
    The O’Leary/Sant questionnaire consists of 2 brief, self-administered indices for measuring lower urinary tract symptoms and their impact in patients with BPS. It assesses severity of symptoms and how much of a problem the symptoms cause for the patient. Symptom and problem index scores are scored from 0 to 20 (0 = no symptoms/problems, 20 = worst symptoms/problems). The symptom index is able to discriminate characteristics between patients and controls (O’Leary et al. 1997). A 1 month recall period was used.
    Units: units on a scale
        arithmetic mean (standard deviation)
    14.2 ± 2.0 13.8 ± 2.2 -
    Baseline Bladder Pain/Interstitial Cystitis Symptom Score
    The Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS) is an 8-item measure (score from 0 to 38; 0 = no burden and 38 = max. burden), developed to identify an appropriate bladder pain syndrome (BPS) population for clinical trials to evaluate new treatments for BPS. Subjects were asked to consider the past seven days. Baseline is defined as the last observation (scheduled or unscheduled) prior to IMP.
    Units: units on a scale
        arithmetic mean (standard deviation)
    30.2 ± 3.1 29.3 ± 3.7 -
    Baseline SF-12 Physical component summary
    The SF-12 acute version is a subset of the SF-36®, whose scoring algorithms involve weighted item responses. The SF-12 acute version has 12 questions covering 8 health domains commonly represented in health surveys: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional, and mental health. Results are expressed in terms of 2 meta-scores: the Physical Component Summary and the Mental Component Summary. The summaries are scored from 0 to 100 . Baseline is defined as the last observation prior to IMP.
    Units: units on a scale
        arithmetic mean (standard deviation)
    35.326 ± 8.391 39.023 ± 7.108 -
    Baseline SF-12 Mental component summary
    The SF-12 acute version is a subset of the SF-36®, whose scoring algorithms involve weighted item responses. The SF-12 acute version has 12 questions covering 8 health domains commonly represented in health surveys: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional, and mental health. Results are expressed in terms of 2 meta-scores: the Physical Component Summary and the Mental Component Summary. The summaries are scored from 0 to 100 . Baseline is defined as the last observation prior to IMP.
    Units: units on a scale
        arithmetic mean (standard deviation)
    37.621 ± 9.737 41.188 ± 10.836 -

    End points

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    End points reporting groups
    Reporting group title
    GRT6010
    Reporting group description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of GRT6010 solution.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 4 instillations (1 instillation at each Treatment Visit) of matching placebo solution.

    Primary: Change in average daily pain scores

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    End point title
    Change in average daily pain scores
    End point description
    The pain scores were assessed on a 0-100 Visual analog scale (VAS) twice daily (morning and evening) using an e-diary. Subjects were asked: “Please indicate how much bladder pain you had on average since the last assessment”. The VAS was labeled with 0 = “no pain” and 100 = “pain as bad as you can imagine”. For this end point, the value reported as arithmetic mean is the posterior mean from the Bayesian analysis with corresponding standard deviations. A probabilistic approach based on Bayesian methodology was used to estimate the probability of a treatment effect. Thus 95% credibility interval (Credibility intervals are used in Bayesian analyses and are analogous to confidence intervals but there are important differences) are reported. The statistical analysis was performed using a Bayesian variant of the MMRM using pain scores as dependent variable. The model accounted for the effects of treatment, time, their interaction, and baseline (as covariate).
    End point type
    Primary
    End point timeframe
    Baseline to end-of-treatment.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [1]
    23 [2]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -21.7 ± 7.35
    -14.3 ± 6.26
    Notes
    [1] - Full Analysis Set
    [2] - Full Analysis Set
    Statistical analysis title
    Change in average daily pain intensity
    Statistical analysis description
    The primary analysis was performed under Bayesian paradigm. Point (mean) and interval estimates (2-sided 95% credibility interval) for the treatment difference to placebo based on the posterior distribution are reported. Baseline was defined as the last 3 days prior to Treatment Visit 1. End of treatment was defined as assessments during the 2 days after the fourth instillation at Treatment Visit 4 (starting with the morning assessment of the next day).
    Comparison groups
    GRT6010 v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.944 [4]
    Method
    Bayesian analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.1
         upper limit
    1.17
    Variability estimate
    Standard deviation
    Dispersion value
    4.46
    Notes
    [3] - The informative prior for the placebo effect followed a normal distribution with a mean of −13 and a variance of 49. All other parameters followed a vague normal distribution, respectively vague truncated normal distributions for the variance. The chosen covariance structure was compound symmetry.
    [4] - This is not a frequentist analysis and the p-value entry is the Bayesian posterior probability. In this case it shows the probability of an effect larger than 0. The effect is the difference of the treatment effect compared to placebo.
    Statistical analysis title
    Sensitivity analysis 1
    Statistical analysis description
    Sensitivity analysis 1 - Adjusting primary analysis using a non-informative prior for the placebo effect.
    Comparison groups
    GRT6010 v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.932 [6]
    Method
    Bayesian analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.95
         upper limit
    1.34
    Variability estimate
    Standard deviation
    Dispersion value
    4.54
    Notes
    [5] - All parameters followed a vague normal distribution, respectively vague truncated normal distributions for the variance, including the placebo effect.
    [6] - This is not a frequentist analysis and the p-value entry is the Bayesian posterior probability. In this case it shows the probability of an effect larger than 0. The effect is the difference of the treatment effect compared to placebo.
    Statistical analysis title
    Sensitivity analysis 2
    Statistical analysis description
    Sensitivity analysis 2 - Adjusting primary analysis using an unstructured covariance matrix.
    Comparison groups
    GRT6010 v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.892 [8]
    Method
    Bayesian analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.05
         upper limit
    3.94
    Variability estimate
    Standard deviation
    Dispersion value
    5.71
    Notes
    [7] - The informative prior for the placebo effect followed a normal distribution with a mean of -13 and a variance of 49. An inverse Wishart distribution was used as prior for the covariance matrix with variance of 1. All other parameters followed a vague normal distribution.
    [8] - This is not a frequentist analysis and the p-value entry is the Bayesian posterior probability. In this case it shows the probability of an effect larger than 0. The effect is the difference of the treatment effect compared to placebo.
    Statistical analysis title
    Sensitivity analysis 3
    Statistical analysis description
    Sensitivity analysis 3 - Adjusting primary analysis using a non-informative prior for the placebo effect as well as an unstructured covariance matrix.
    Comparison groups
    GRT6010 v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.882 [10]
    Method
    Bayesian analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.97
         upper limit
    4.07
    Variability estimate
    Standard deviation
    Dispersion value
    5.64
    Notes
    [9] - An inverse Wishart distribution was used as prior for the covariance matrix with variance of 1. All other parameters followed a vague normal distribution.
    [10] - This is not a frequentist analysis and the p-value entry is the Bayesian posterior probability. In this case it shows the probability of an effect larger than 0. The effect is the difference of the treatment effect compared to placebo.

    Secondary: Plasma concentrations of GRT6010

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    End point title
    Plasma concentrations of GRT6010 [11]
    End point description
    Plasma samples were analyzed to determine concentrations of GRT6010, using validated bioanalytical assays. Pre-dose concentrations of GRT6010 above the lower limit of quantification were reported for all visits in almost all subjects are reported for all visits following the first instillation.
    End point type
    Secondary
    End point timeframe
    Blood samples for pharmacokinetic assessment were taken less than 30 min before IMP administration and 2 hours (± 15 min) after IMP administration (4 treatment visits).
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations of GRT6010 were analyzed and reported.
    End point values
    GRT6010
    Number of subjects analysed
    31 [12]
    Units: pg/mL
    arithmetic mean (standard deviation)
        Treatment Visit 1, 2h post-dose (N = 21)
    308 ± 488
        Treatment Visit 2, pre-dose (N = 29)
    232 ± 266
        Treatment Visit 2, 2h post-dose (N = 20)
    600 ± 647
        Treatment Visit 3, pre-dose (N = 30)
    398 ± 386
        Treatment Visit 3, 2h post-dose (N = 24)
    677 ± 693
        Treatment Visit 4, pre-dose (N = 30)
    526 ± 540
        Treatment Visit 4, 2h post-dose (N = 24)
    881 ± 867
        Follow-up Visit (N = 30)
    708 ± 794
        End-of-trial Visit (N = 25)
    222 ± 273
    Notes
    [12] - Pharmacokinetic Set
    No statistical analyses for this end point

    Secondary: Change in average pain intensity over the last 12 hours

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    End point title
    Change in average pain intensity over the last 12 hours
    End point description
    The pain scores were assessed on a 0-100 Visual analog scale (VAS) twice daily (morning and evening) using an e-diary. Subjects were asked: “Please indicate how much bladder pain you had on average since the last assessment”. The VAS was labeled with 0 = “no pain” and 100 = “pain as bad as you can imagine”. Analysis including only the last assessment on the 2 days after Treatment Visit 4 using an ANCOVA-like model with a Bayesian approach. For this end point, the value reported as arithmetic mean is the posterior mean from the Bayesian analysis with corresponding standard deviations. The informative prior for the placebo effect followed a normal distribution with a mean of -13 and a variance of 49. All other parameters followed a vague normal distribution, respectively vague truncated normal distribution for the variance.
    End point type
    Secondary
    End point timeframe
    Baseline to end-of-treatment.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [13]
    23 [14]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -19.0 ± 8.69
    -14.8 ± 6.85
    Notes
    [13] - Full Analysis Set
    [14] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Change in average number of daily micturition

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    End point title
    Change in average number of daily micturition
    End point description
    Average number of daily micturition at Baseline is calculated as the number of micturitions averaged over the last 3 days prior to Treatment Visit 1. Average number of daily micturition after Treatment Visit 4 (end-of-treatment) is the average number during the 2 days following instillation/Treatment Visit (starting with the morning assessment of the next day).
    End point type
    Secondary
    End point timeframe
    Baseline to end-of-treatment.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [15]
    23 [16]
    Units: number of micturition
        arithmetic mean (standard deviation)
    -2.2 ± 4.2
    -1.9 ± 3.2
    Notes
    [15] - Full Analyses Set (N = 27)
    [16] - Full Analyses Set (N = 20)
    No statistical analyses for this end point

    Secondary: Change in average daily urine volume per voiding

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    End point title
    Change in average daily urine volume per voiding
    End point description
    Average daily urine volume per voiding at baseline was calculated as the volume per voiding over the last 3 days prior to Treatment Visit 1. Average daily urine volume per voiding after the End-of-Treatment Visit was the average during the 2 days following instillation/Treatment Visit (starting with the morning assessment of the next day).
    End point type
    Secondary
    End point timeframe
    Baseline to end-of-treatment.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [17]
    23 [18]
    Units: milliliter(s)
        arithmetic mean (standard deviation)
    26.0 ± 33.0
    -7.9 ± 41.1
    Notes
    [17] - Full Analyses Set (N = 24)
    [18] - Full Analyses Set (N = 15)
    No statistical analyses for this end point

    Secondary: Change in average daily intensity of urgency

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    End point title
    Change in average daily intensity of urgency
    End point description
    Intensity of urgency was assessed on a 0–100 VAS twice daily (morning and evening). Average daily intensity of urgency at baseline was calculated as the intensity of urgency averaged over the last 3 days prior to Treatment Visit 1. Average daily intensity of urgency after the End-of-Treatment Visit was the average during the 2 days following the instillation/Treatment Visit (starting with the morning assessment of the next day). The VAS was labeled with 0 = “no urgency” and 100 = “urgency as bad as you can imagine”.
    End point type
    Secondary
    End point timeframe
    Baseline to end-of-treatment.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [19]
    23 [20]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -19.3 ± 19.6
    -16.5 ± 17.2
    Notes
    [19] - Full Analysis Set (N = 29)
    [20] - Full Analysis Set (N = 21)
    No statistical analyses for this end point

    Secondary: Change in O'Leary/Sant questionnaire (Symptom Index)

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    End point title
    Change in O'Leary/Sant questionnaire (Symptom Index)
    End point description
    The O’Leary/Sant questionnaire consists of 2 brief, self-administered indices for measuring lower urinary tract symptoms and their impact in patients with bladder pains syndrome (BPS). It assesses the severity of symptoms and how much they bother the patient. Symptom and problem index scores are scored from 0 to 20 (0 = no symptoms/problems, 20 = worst symptoms/problems). The symptom index is able to discriminate characteristics between patients and controls (O’Leary et al. 1997). A recall period of 3 days was used.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up visit.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [21]
    23 [22]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -5.5 ± 4.0
    -3.7 ± 3.8
    Notes
    [21] - Full Analyses Set (N = 24)
    [22] - Full Analyses Set (N = 20)
    No statistical analyses for this end point

    Secondary: Change in O'Leary/Sant questionnaire (Problem Index)

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    End point title
    Change in O'Leary/Sant questionnaire (Problem Index)
    End point description
    The O’Leary/Sant questionnaire consists of 2 brief, self-administered indices for measuring lower urinary tract symptoms and their impact in patients with bladder pains syndrome (BPS). It assesses the severity of symptoms and how much they bother the patient. Symptom and problem index scores are scored from 0 to 20 (0 = no symptoms/problems, 20 = worst symptoms/problems). The symptom index is able to discriminate characteristics between patients and controls (O’Leary et al. 1997). A recall period of 3 days was used.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up visit.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [23]
    23 [24]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -4.8 ± 3.6
    -3.3 ± 3.4
    Notes
    [23] - Full Analyses Set (N = 24)
    [24] - Full Analyses Set (N = 20)
    No statistical analyses for this end point

    Secondary: Change in Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS)

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    End point title
    Change in Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS)
    End point description
    The Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS) is an 8-item measure (score from 0 to 38; 0 = no burden and 38 = max. burden), developed to identify an appropriate bladder pain syndrome (BPS) population for clinical trials to evaluate new treatments for BPS. Subjects were asked to consider the past seven days.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up visit.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [25]
    23 [26]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -8.7 ± 5.9
    -7.4 ± 5.9
    Notes
    [25] - Full Analyses Set (N = 30)
    [26] - Full Analyses Set (N = 22)
    No statistical analyses for this end point

    Secondary: 12-Item Short Form Health Survey (Physical component summary)

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    End point title
    12-Item Short Form Health Survey (Physical component summary)
    End point description
    The SF-12 acute version is a subset of the SF-36®, whose scoring algorithms involve weighted item responses. The SF-12 acute version has 12 questions covering 8 health domains commonly represented in health surveys: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional, and mental health. Results are expressed in terms of 2 meta-scores: the Physical Component Summary and the Mental Component Summary. Physical and mental component summaries are scored from 0 to 100.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up visit.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [27]
    23 [28]
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.512 ± 8.020
    4.723 ± 4.624
    Notes
    [27] - Full Analysis Set (N = 30)
    [28] - Full Analysis Set (N = 22)
    No statistical analyses for this end point

    Secondary: 12-Item Short Form Health Survey (Mental component summary)

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    End point title
    12-Item Short Form Health Survey (Mental component summary)
    End point description
    The SF-12 acute version is a subset of the SF-36®, whose scoring algorithms involve weighted item responses. The SF-12 acute version has 12 questions covering 8 health domains commonly represented in health surveys: physical functioning, role functioning physical, bodily pain, general health, vitality, social functioning, role functioning emotional, and mental health. Results are expressed in terms of 2 meta-scores: the Physical Component Summary and the Mental Component Summary. Physical and mental component summaries are scored from 0 to 100.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up visit.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [29]
    23 [30]
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.930 ± 9.179
    2.947 ± 8.931
    Notes
    [29] - Full Analysis Set (N = 30)
    [30] - Full Analysis Set (N = 22)
    No statistical analyses for this end point

    Secondary: Patient's Global Impression of Change (PGIC)

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    End point title
    Patient's Global Impression of Change (PGIC)
    End point description
    The 7-point Patient's Global Impression of Change (PGIC) is a complementary assessment of analgesic efficacy. Subjects respond to the question “Since the start of the trial, my overall status is:” with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse). A response of very much improved or much improved is generally regarded as a clinically important outcome. PGIC was assessed at the End-of-trial visit or, in case of premature discontinuation, the End-of-trial for discontinued subjects.
    End point type
    Secondary
    End point timeframe
    End of the trial.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [31]
    23 [32]
    Units: Subjects
        Very much improved
    1
    1
        Much improved
    8
    6
        Minimally improved
    8
    4
        No change
    11
    12
        Minimally worse
    3
    0
        Much worse
    0
    0
        Very much worse
    0
    0
        Missing
    0
    0
    Notes
    [31] - Full Analysis Set
    [32] - Full Analysis Set
    No statistical analyses for this end point

    Secondary: Clinician's Global Impression of Change (CGIC)

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    End point title
    Clinician's Global Impression of Change (CGIC)
    End point description
    The investigators were rating the subject’s global improvement and satisfaction with the treatment on a 7-point scale that ranges from “very much improved” to “very much worse” with “no change” as the mid-point. The CGIC (Schneider et al. 1997) was chosen as a complementary assessment of analgesic efficacy. CGIC was assessed at the End-of-trial visit or, in case of premature discontinuation, the End-of-trial for discontinued subjects.
    End point type
    Secondary
    End point timeframe
    End of the trial.
    End point values
    GRT6010 Placebo
    Number of subjects analysed
    31 [33]
    23 [34]
    Units: Subjects
        Very much improved
    0
    1
        Much improved
    15
    6
        Minimally improved
    10
    6
        No change
    5
    9
        Minimally worse
    1
    1
        Much worse
    0
    0
        Very much worse
    0
    0
        Missing
    0
    0
    Notes
    [33] - Full Analysis Set
    [34] - Full Analysis Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were documented from the time of enrollment (i.e., the time the informed consent form is signed) up to the time of the last protocol scheduled contact, i.e., date of last visit/contact.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    GRT6010
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    GRT6010 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 23 (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: 0%
    Non-serious adverse events
    GRT6010 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 31 (41.94%)
    9 / 23 (39.13%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Medical device pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Vulvovaginal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Burn oral cavity
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    4
    Post-traumatic pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Laryngeal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Migraine
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 23 (0.00%)
         occurrences all number
    6
    0
    Dry mouth
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Dysuria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    5 / 31 (16.13%)
    5 / 23 (21.74%)
         occurrences all number
    5
    5
    Vaginal infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Vulvitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2017
    Amendment 01 of 29 Mar 2017 The protocol was amended based on feedback from the German Federal Institute for Drugs and Medical Devices and the ethics committee in Munich, Germany. Major changes are listed here. • Exclusion criteria and discontinuation criteria based on corrected QT interval (QTc) prolongation and liver parameters were defined. • Twelve-lead ECG recordings were added at Treatment Visit 1, Treatment Visit 2, Treatment Visit 3, and Treatment Visit 4. • The time window for the diagnostic cystoscopy with hydrodistension was extended. • Reference to the anesthesia required for the diagnostic cystoscopy with hydrodistension was made. • Details pertaining to preparation of IMP prior to instillation were added. • Rationale for the dose selection was added. • The sponsor’s medically qualified person and signatory were updated.

    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.
    Ninety subjects were planned to be treated in the trial. Owing to slow recruitment, fewer subjects than planned were treated. At the time at which the trial was terminated, 54 subjects had been treated.
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