Study to Determine Pharmacodynamic Effects and Pharmacokinetics of KUC 7483 CL in Patients With Spinal Cord Injury and Neurogenic Detrusor Overactivity

Study Overview
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Brief Summary
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Study to investigate pharmacodynamic effects and pharmacokinetics of KUC 7483

Official Title
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A Phase I, Randomised, Double-blind, Placebo-controlled Study to Determine Pharmacodynamic Effects and Pharmacokinetics of a Single Oral Dose of 320 mg KUC 7483 CL in Patients With Spinal Cord Injury and Neurogenic Detrusor Overactivity

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Drug: KUC 7483 CL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male patients with acquired suprasacral spinal cord injury practicing intermittent catheterization under stable condition as determined by the investigator Recovery from spinal shock in posttraumatic patients Aged 18 - 70 years BMI range ≥ 18.5 and < 29.9 kg/m2 Documented neurogenic detrusor overactivity as shown by urodynamics within the last 12 months prior to study start and confirmation by the baseline urodynamics (day 2). Detrusor overactivity is defined as a non-volitional increase in detrusor pressure of > 6 cm H2O. Detrusor sphincter dyssynergia may be facultative Written informed consent consistent with International committee on harmonization (ICH)/ Good Clinical Practice (GCP) and local legislation given prior to any study procedures Ability and willingness to comply with study treatment regimen and to attend study Exclusion Criteria: A total daily volume of urine > 3000 ml as verified in the micturition diary before randomization Treatment with drugs with known anticholinergic effect on the detrusor and/or alpha-blockers, 7 days prior to inclusion visit 2 Treatment with botulinus toxin, capsaicin or resiniferatoxin in the last 6 months prior to the study Unstable dosage of any drug or the expectation of initiation of such a treatment during the trial Use of agonists or antagonists at beta-adrenoceptors (The following drugs may nevertheless be used since they do not act upon beta-3 adrenoceptors in therapeutic doses: atenolol, bisoprolol, carvedilol, metoprolol, propranolol, salbutamol and salmeterol) Neurological diseases other than suprasacral spinal cord injury, affecting urinary bladder function Significant stress incontinence as determined by the investigator Non-functional bladder outlet obstruction as determined by the investigator Dilatation of the upper urinary tract Low compliance bladder (Compliance < 20 mL/cm H2O) Detrusor hyporeflexia/areflexia and bradykinesia/tremor of the external urethral sphincter Prostatic or bladder carcinoma Acute urinary tract infection during the run-in period or during study period History of interstitial cystitis Surgery of the prostate, the urinary bladder, the urethra, and thermotherapy, ultrasound or laser therapy of the prostate for 12 months prior to enrolment to the study Pelvic radiation therapy Use of indwelling catheter Any electro stimulation therapy within the 14 days prior to inclusion visit 2 Significant hepatic or renal disease defined as twice the upper limit of the reference range, regarding serum concentrations of Aspartate transaminase ((SGOT) (AST)), Alanine transaminase ((SGPT) ALT)), Alkaline phosphatase (ALP), and/or creatinine > 1.4 mg/dl Diseases or any condition, in which treatment with ß3-adrenoceptors agonists is contraindicated Participation in another clinical trail 8 weeks preceding to enrolment in this study or during study period Patients with any severe medical or any other condition which in the opinion of the investigator makes the patient unsuitable for inclusion Allergic to KUC-7483 or its excipients Patients with Diabetes mellitus type 1 or 2 treated with oral antidiabetic drugs or insulin (any formulation)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KUC 7483 CL<br> | Drug: KUC 7483 CL<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in volume at first contraction |  | 2 hours post dosing | 
| Change from baseline in volume at first contraction |  | 6 hours post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Detrusor pressure at first contraction |  | 2 and 6 hours post dosing | 
| Change from baseline in Maximum amplitude of involuntary detrusor contraction |  | 2 and 6 hours post dosing | 
| Change from baseline in Volume at first incontinence episode |  | 2 and 6 hours post dosing | 
| Change from baseline in compliance |  | 2 and 6 hours post dosing | 
| Change from baseline in Maximum cystometric capacity |  | 2 and 6 hours post dosing | 
| Change from baseline in Detrusor pressure at maximum flow induced by triggering |  | 2 and 6 hours post dosing | 
| Change from baseline in Post-triggering residual urinary volume |  | 2 and 6 hours post dosing | 
| AUC0-∞ (area under the concentration time curve of KUC 7322 ZW in plasma over the time interval from 0 extrapolated to infinity) |  | up to 24 hours post dosing | 
| Cmax (maximum concentration of KUC 7322 ZW in plasma) |  | up to 24 hours post dosing | 
| AUC0-tz (area under the concentration-time curve of KUC 7322 ZW in plasma over the time interval from 0 to the time of the last quantifiable data point) |  | up to 24 hours post dosing | 
| AUC0-24 (Area under the concentration time curve of KUC 7322 ZW in plasma over the time interval 0 to 24 hours) |  | up to 24 hours post dosing | 
| tmax (time from dosing to the maximum concentration of KUC 7322 ZW in plasma) |  | up to 24 hours post dosing | 
| λz (terminal rate constant of KUC 7322 ZW in plasma) |  | up to 24 hours post dosing | 
| t1/2 (terminal half-life of KUC 7322 ZW in plasma) |  | up to 24 hours post dosing | 
| MRTpo (mean residence time of KUC 7322 ZW in the body after po administration) |  | up to 24 hours post dosing | 
| CL/F (apparent clearance of KUC 7322 ZW in the plasma after extravascular administration) |  | up to 24 hours post dosing | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose) |  | up to 24 hours post dosing | 
| Aet1-t2 (amount of KUC 7322 ZW that is eliminated in urine from the time interval t1 to t2) |  | up to 24 hours post dosing | 
| fet1-t2 (fraction of administered drug excreted unchanged in urine from time point t1 to t2) |  | up to 24 hours post dosing | 
| CLR,t1-t2 (renal clearance of KUC 7322 ZW in plasma from the time point t1 until the time point t2) |  | up to 24 hours post dosing | 
| Number of patients with adverse events |  | up to 26 days | 
| Number of patients with clinically significant changes in vital signs | Blood Pressure | up to 24 hours post dosing | 
| Assessment of tolerability by investigator on a 4-point scale |  | 10 days post dosing | 
| Assessment of tolerability by patient on a 4-point scale |  | 10 days post dosing |