Clinical trial NCT03149809: Behavioral or Solifenacin Therapy for Urinary Symptoms in Parkinson Disease
Official title: Behavioral or Solifenacin Therapy for Urinary Symptoms in Parkinson Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Overactive Bladder
Parkinson Disease
Keywords: Urinary incontinence
Parkinson disease
Overactive urinary bladder
Nocturia
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2017-05-11
Enrollment: 77
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Controlled Non-Inferiority Trial
Primary purpose: TREATMENT

Brief summary: The impact of urinary symptoms in Parkinson disease (PD) extends beyond worsened well-being. Urinary symptoms common in PD, especially incontinence and nocturia, are major risk factors for falls likely due to the combination of urinary urgency and impaired mobility (and falls are a leading cause of mortality in PD), for spouse/caregiver stress due to decreased mutuality in the relationship, and for institutionalization, largely due to increased disability. Additionally, most medications currently recommended for urinary symptoms in PD are anticholinergic and have the potential to worsen the progressive cognitive and autonomic burdens of the disease. Veterans with PD are also more likely to rely solely on VA for their health care than Veterans without PD. Thus, optimizing the care of urinary symptoms for Veterans with PD becomes imperative, particularly for VA. Using a non-inferiority design, this proposal seeks to demonstrate the comparative effectiveness of pelvic floor muscle exercise-based behavioral therapy versus drug therapy to treat urinary symptoms in PD.

Detailed description: The number of persons with Parkinson Disease (PD) in the United States is expected to double by 2030 as the population ages. Importantly, this increase in the prevalence of PD will have greater impact within the Department of Veterans Affairs (VA) because the Veteran population is older than the general population and Veterans with PD are more likely than those without PD to rely solely on VA for their health care. While PD is often characterized by the motor symptoms of the disease (tremor, bradykinesia, rigidity), non-motor symptoms such as urinary symptoms correlate more closely with impaired well-being as the disease progresses. However, the impact of urinary symptoms in PD extends beyond worsened well-being. The urinary symptoms of overactive bladder (OAB), including urgency, frequency, and nocturia, with or without urinary incontinence, are the most common urinary symptoms of PD. OAB symptoms are associated with falls (a cause of increased mortality in PD), with spouse/caregiver stress, and, ultimately with institutionalization, thus it is critical that we optimize the care of urinary symptoms for Veterans with PD.

Several studies suggest abnormal central nervous system processing of sensory input from bladder afferent nerves contributes to OAB symptoms in PD, possibly because of delayed recognition of bladder fullness. This mirrors findings in non-PD populations with OAB. In the non-PD OAB population, pelvic floor muscle contractions diminish bladder muscle contraction and recent evidence demonstrates that behavioral training with pelvic floor muscle exercises improves the cortical integration of bladder afferent signals. Pelvic floor muscle exercise-based behavioral therapy for OAB symptoms requires individuals to learn a motor skill and implement an adaptive behavioral strategy to delay the need to void. Because of its effectiveness compared to drug therapy, pelvic floor muscle exercise-based behavioral therapy is recommended first-line in men and women with OAB who do not have PD. However, the most recent clinical guidelines for the treatment of urinary symptoms in PD recommend treatment with anticholinergic drugs. While some anticholinergic drugs are effective in reducing symptoms of OAB, it is important to note that there is a glaring lack of an empirical evidence base to promote these drugs in the setting of PD given that they add to the anticholinergic burden of antiparkinsonian therapy, and may worsen the cognitive and autonomic burdens of the illness. Therefore, randomized controlled trials (RCTs) are needed to optimize treatment paradigms for urinary symptoms in PD.

The investigators propose a three-site, RCT conducted at the Atlanta (lead site), Birmingham and Richmond VA's to establish non-inferiority of pelvic floor muscle exercise-based behavioral therapy compared to drug therapy for OAB symptoms in adults with PD. Groups will be stratified by OAB symptom severity, PD motor symptom severity, gender, and site. The investigators will randomize 90 participants in order to complete the study in 80 participants, assuming 85% power and a non-inferiority margin for the OAB symptom score of 15% at 12-weeks. The primary outcome measure will be urinary symptom severity as measured by the International Consultation on Incontinence Questionnaire (ICIQ)-OAB symptom score collected at 3 time points during the study: baseline, 6 weeks, and 12 weeks. The investigators' benchmark for successful treatment will be a 2 point reduction in the ICIQ-OAB symptom score, which corresponds with perceived benefit in preliminary studies of behavioral therapy treatment for OAB symptoms in PD. To evaluate the primary efficacy outcome, the investigators will utilize a random effects mixed model and adjust for baseline OAB symptom score severity. Additionally, in order to better understand central control mechanisms of bladder function, the investigators will determine if domain-specific cognitive function impacts the response to exercise-based behavioral therapy or drug therapy for urinary symptoms. At baseline and 12 weeks, randomized participants will undergo a brief neuropsychological battery. Understanding how domain-specific cognitive function impacts response to treatment may inform new targets for rehabilitation therapy.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of PD determined by a board-certified neurologist with specialty training in movement disorders
* An ICIQ-OAB Symptom Score of 7, which indicates clinically significant symptoms of OAB, defined as presence of urinary urgency with or without urgency incontinence usually with increased daytime frequency and nocturia in the absence of infection or other obvious pathology

Exclusion Criteria:

* Significant cognitive impairment, as indicated by a Montreal Cognitive Assessment (MoCA) score of \< 18, which is the recommended diagnostic cutpoint for dementia in PD.
* Previous intensive pelvic floor muscle exercise training
* Clinically significant depression as measured by a Geriatric Depression Scale-Short Form score 10 which could affect motivation to fully engage in the intervention
* Use of an indwelling urinary catheter
* Post-void residual (PVR) urine measurement by bladder ultrasound of 150 mL
* Severe uterine prolapse past the vaginal introitus
* Poorly controlled diabetes defined by a hemoglobin A1c (HgbA1c) of \>9.0% within the last 3 months. Participants with poorly controlled diabetes will be offered enrollment if the OAB symptoms persist after improvement in diabetes control
* Chronic renal failure and on hemodialysis
* Genitourinary cancer with ongoing surgical or external beam radiation treatment
* Previous artificial urinary sphincter, sling procedure or implanted sacral neuromodulation device
* History of bladder-injection of botulinum toxin in the last 12 months
* Any unstable health condition expected to result in hospitalization or death within in the next 3 months as determined by site principal investigator.
* Hypersensitivity to drug class
* Contraindication to the study drug (solifenacin) including: narrow angle glaucoma, history of gastric retention, history of acute urinary retention requiring catheterization
* Current use of a bladder relaxant - permitted to enroll after two week washout
* Hematuria on microscopic examination in the absence of infection. A urologic consultation will be recommended and enrollment will depend on clearance by a urologist and agreement by the site PI that entry into the treatment protocol is not contraindicated
* If on diuretic, dose should be stable for at least 4 weeks
* If taking an alpha-blocker, dose should be stable for at least 4 weeks
* If taking dutasteride or finasteride, dose should be stable for at least 6 months

Primary outcomes:
measure: ICIQ-OAB Questionnaire
timeFrame: ICIQ-OAB Symptom score at 12 weeks
Secondary outcomes:
measure: Bladder Diary
timeFrame: Incontinence episodes per day at 12 weeks
measure: ICIQ-OAB QOL
timeFrame: ICIQ-OAB QOL score at 12 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham VA Medical Center, Birmingham, AL
state: Alabama
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center, Richmond, VA
state: Virginia
Study officials:
affiliation: Atlanta VA Medical and Rehab Center, Decatur, GA
name: Elizabeth Camille Vaughan, MD MS
role: PRINCIPAL_INVESTIGATOR
References: