E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neurogenic detrusor overactivity in patients with spinal cord injury |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To compare a single oral dose of tolterodine (2 mg) with placebo on the reduction of uninhibited detrusor contractions induced by provocation testing. |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety of tolterodine administration in patients with spinal cord injury and pathology. 2. To explore relationships of the efficacy variables with serum concentrations of tolterodine and/or its active metabolite, DD 01. |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Male or female patients aged 18-65 years, with urodynamic evidence of neurogenic detrusor overactivity (phasic or uninhibited detrusor contraction) arising as a consequence of spinal cord injury or pathology. 2. Evidence of phasic uninhibited detrusor contraction on fast fill cystometry at the beginning of Period 1. 3. Demonstrable provoked uninhibited detrusor contraction following force fill at the beginning of Period 1. 4. Subjects capable of understanding and giving written informed consent after full discussion concerning the nature of the research. 5. Female subjects must have a negative pregnancy test. 6. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial. 7. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
|
|
E.4 | Principal exclusion criteria |
1. Subjects who do not provide written consent to participate in the study 2. Subjects who have a medical condition that would impair their ability to participate reliably in the study. 3. Subjects who are pregnant or lactating. 4. Subjects with a recent history of autonomic dysreflexia (AD) or AD which is associated with urodynamic investigations 5. Treatment within 7 days (or 5x plasma half-life, if longer) preceding the study, or expected to start treatment during the study with: a. anticholinergic drugs b. drugs with significant anticholinergic effects such as tricyclic antidepressants c. drug treatment for overactive bladder. Estrogen treatment initiated more than 2 months prior to randomization is allowed. 6. Use of inhibitors of the metabolism of tolterodine: a. Potent cytochrome P450 3A4 inhibitors such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole and itraconazole), cimetidine, MAOIs, and protease inhibitors. Drugs and/or herbal preparations capable of inducing hepatic enzyme metabolism (e.g., barbiturates, rifampin, carbamazepine, phenytoin, primidone or St. John’s Wort). These must be discontinued within 30 days (or 5 half-lives of inducing/inhibiting agent, whichever is longer) of enrollment in the study. b. Fluoxetine must be discontinued at least 5 weeks before first dose of study medication. c. Have consumed grapefruit or grapefruit-containing products within 7 days prior to the first dose of study medication 7. Subject on a variable dosage of any drug with anticholinergic side effects, or subject expected to start such treatment during the study. 8. Have a known history of hypersensitivity, allergy, severe adverse drug reaction or intolerance to anticholinergic drugs, including tolterodine. 9. Have contraindications to the use of anticholinergic drugs, e.g., uncontrolled narrow-angle glaucoma, urinary retention, significant urinary outflow obstruction (not including sphincter dyssynergia), gastric retention. Significant urinary outflow obstruction is defined as being a urinary pressure/flow study in the obstructed range of the Abrams/Griffiths nomogram or a maximum urinary flow rate <15 mL/sec. 10. Subjects who have evidence of alcohol abuse or abuse of controlled substances. 11. Subject who has received any electrostimulation or bladder retraining within the three months before randomization, or is expected to start such therapy during the study period. 12. Chronic persistent local pathology that may lead to urinary symptoms e.g. urinary tract infection, marked cystocele or pelvic prolapse, interstitial cystitis, bladder stones, unexplained hematuria (> 1+ on dipstick test unless fully investigated prior to randomization to exclude significant urological disease). 13. Have a clinically significant ECG abnormality at screening, except those with non-clinically significant sinus tachycardia or sinus bradycardia. Screening 12-lead ECG demonstrating QTC>430 msec (males) and QTc>450 msec (females). 14. History or evidence of major hematological, renal or hepatic abnormalities (subjects with clinically significant hepatic (Child Pugh C classification) or significant renal impairment serum creatinine 3xULN).
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Area under the pressure curve of the provoked detrusor contraction |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of trial is defined when 8 patients have completed visit 1,2,3, and the follow up telephone visit |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |