Protocol for a phase II, open-label exploratory study investigating the efficacy of fesoterodine for treatment of adult patients with spinal cord injury suffering from neurogenic detrusor overactivity for amelioration of autonomic dysreflexia

Abstract

Introduction: Managing and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals. However, individuals with spinal cord injury (SCI) at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from neurogenic detrusor overactivity (NDO). Treatment of NDO would not only improve lower urinary tract function but could also reduce the severity and frequency of life-threatening episodes of AD. Fesoterodine, an antimuscarinic drug, has been successfully employed as a first-line treatment for detrusor overactivity in individuals without an underlying neurological disorder. Thus, our aim is to investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI.

Methods and analysis: This phase II, open-label exploratory, non-blinded, non-randomised, single-centre study will investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6. During screening, we will interview potential candidates (with a previous history of NDO and AD) and assess their injury severity. At baseline, we will perform cardiovascular and cerebrovascular monitoring (blood pressure (BP), heart rate and cerebral blood flow velocity) during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to assess severity and frequency of AD episodes (ie, maximum increase in systolic BP). The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy. To answer this, we will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, ie, three cycles of 4 weeks each). At the end of each treatment cycle, participants will be asked to answer standardised questionnaires (AD symptoms and quality of life) and present bladder and bowel diaries, which will provide additional subjective information.

Ethics and dissemination: The University of British Columbia Research Ethics Boards (H15-02364), Vancouver Coastal Health Research Institute (V15-02364) and Health Canada (205857) approved this study. The findings of the study will be published in peer-reviewed journals and presented at national and international scientific meetings. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials and CONsolidated Standards Of Reporting Trials statements.

Trial registration number: NCT02676154; Pre-results.

Keywords: autonomic dysreflexia; fesoterodine; neurogenic detrusor overactivity; open-label study; protocol; spinal cord injury.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study timeline. The study timeline is showing each study visit and the expected duration of study participation. *The follow-up visit should be conducted via telephone 4 weeks following the end of treatment (ie, visit 6) or last scheduled visit in case of early termination of treatment.

Figure 2

Drug administration protocol. Beginning of treatment at visit 3. Eligible individuals will receive a 4-week supply of 4 mg daily doses of fesoterodine. They will also receive instructions for use of medication and reporting adverse events. During the treatment period, individuals will return to the clinic, at least 2 days before their supply runs out, for visits 4 and 5. During these visits, individuals will be assessed for dose efficacy. In consultation with the investigator, individuals will have a choice to either increase the dose of the study drug to 8 mg (green arrow) or stay at the same dose. Individuals who elect to increase their dose to 8 mg per day may return to 4 mg at any time (red arrow). However, individuals may only increase their dose once. Meaning that following a dose reduction, no increases in dose will be permitted. Up to 14 days before the end of treatment period (ie, visit 6), individuals will undergo treatment efficacy evaluations in comparison to baseline (ie, visit 2).

Figure 3

Protocol for the evaluation of autonomic dysreflexia (AD) during urodynamic studies. After arrival and a 5 min rest, blood pressure (BP) and heart rate (HR) measurements will be recorded three times from the right brachial cuff. The individual will be placed in the urodynamic studies (UDS) chair in a supine position. After another 5 min rest, BP and HR measurements will be recorded again three times from the right brachial cuff. Thereafter, urethral and rectal measuring catheters will be inserted. Episodic BP/HR measurement and monitoring for symptoms of AD will be assessed at given time points (ie, start of bladder filling, first sensation, first urge/desire, strong urge/desire or leakage point). In addition, we will continuously record the following: cardiovascular changes ‘beat-to-beat’ of BP and HR from the left finger cuff, electrocardiography and cerebral blood flow. In case of prolonged AD after UDS, BP/HR measurements will be continued until SBP returns to a value below the individual’s threshold for AD. CIC, clean intermittent catheterisation.