KF6010-02

Grünenthal GmbH

Zieglerstr. 6, Aachen, Germany, 52078

Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com

Grünenthal Trial Information Desk, Grünenthal GmbH, 49 2415693223, Clinical-Trials@grunenthal.com

No

No

No

Final

11 Jan 2019

Yes

02 May 2018

Yes

02 May 2018

Yes

Evaluate the efficacy of intravesical instillation of GRT6010 on pain.

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.

26 Jul 2017

No

No

Poland: 71

Germany: 6

77

77

0

0

0

0

0

0

67

10

0

Overall trial (overall period)

Randomised - controlled

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.

Yes

GRT6010 solution for instillation

Concentrate for intravesical solution

Intravesical use

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.

Matching placebo solution for instillation

Concentrate for intravesical solution

Intravesical use

10 ml of a placebo solution were instilled in the bladder at each of the 4 Treatment Visits via single use bladder catheters.

GRT6010

Placebo

GRT6010

Placebo

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).

Primary

Baseline to end-of-treatment.

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).

GRT6010 v Placebo

54

Pre-specified

-7.3

2-sided

Standard deviation

4.46

Sensitivity analysis 1 - Adjusting primary analysis using a non-informative prior for the placebo effect.

GRT6010 v Placebo

54

Pre-specified

-6.9

2-sided

Standard deviation

4.54

Sensitivity analysis 2 - Adjusting primary analysis using an unstructured covariance matrix.

GRT6010 v Placebo

54

Pre-specified

-7

2-sided

Standard deviation

5.71

Sensitivity analysis 3 - Adjusting primary analysis using a non-informative prior for the placebo effect as well as an unstructured covariance matrix.

GRT6010 v Placebo

54

Pre-specified

-6.6

2-sided

Standard deviation

5.64

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.

Secondary

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).

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.

Secondary

Baseline to end-of-treatment.

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).

Secondary

Baseline to end-of-treatment.

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).

Secondary

Baseline to end-of-treatment.

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”.

Secondary

Baseline to end-of-treatment.

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.

Secondary

Baseline to follow-up visit.

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.

Secondary

Baseline to follow-up visit.

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.

Secondary

Baseline to follow-up visit.

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.

Secondary

Baseline to follow-up visit.

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.

Secondary

Baseline to follow-up visit.

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.

Secondary

End of the trial.

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.

Secondary

End of the trial.

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.

21.0

GRT6010

Placebo