RANDOMISED CONTROLLED TRIAL of Transcutaneous Stimulation of the Tibial Nerve for urinary problems associated with Parkinson’s: PRELIMINARY RESULTS OF The STARTUP trial

McClurg D1, Panicker J2, Walker R3, Cunnington A4, Deane K5, Mason H6, Collins M7, Elders A1, Harari D8, Booth J9, Sellers C1, Stratton S1, McArthur J1, Hagen S1

Research Type

Clinical

Abstract Category

Neurourology

Abstract 314
On Demand Neurourology
Scientific Open Discussion Session 24
On-Demand
Clinical Trial Conservative Treatment Neuromodulation
1. NMAHP RU, Glasgow Caledonian University, 2. National Hospital for Neurology and Neurosurgery, 3. North Tyneside PCT, 4. Glasgow Royal Infirmary, 5. School of Health Sciences, University of East Anglia, 6. Yunus Centre Glasgow Caledonian University, 7. Yunus Centre Glasgow Caledonian Univeristy, 8. Guy's and St Thomas' NHS Foudation Trust, 9. School of Life and Health Sciences, Glasgow Caledonian University
Presenter
D

Doreen McClurg

Links

Abstract

Hypothesis / aims of study
Parkinson’s (PD) is characterised predominantly by motor complaints such as bradykinesia, rigidity,  tremor and restricted mobility.  However, non-motor symptoms such as lower urinary tract (LUT) dysfunction are common (80%) (1) increasing the risk for falls, with a negative impact on health-related costs and quality of life.
Previous studies have shown that applying mild electrical stimulation to the tibial nerve at the ankle, using a needle, known as percutaneous tbial nerve stimulation, can improve LUT symptoms in neurological patients including people with PD and thus improve their quality of life.
Our aim was to evaluate the clinical effectiveness and cost-effectiveness of using an adhesive surface electrode to provide transcutaneous tibial nerve stimulation (TTNS), to treat LUT symptoms in people with PD.
Study design, materials and methods
STARTUP was a parallel two−arm, multi-centre, pragmatic, double-blinded, randomised controlled trial. Participants were recruited via the National Health Service and Parkinson’s UK and seen at 12 centres throughout the UK. Remote randomisation, using a computer-generated system to either the TTNS intervention or the non-active (placebo) arm was undertaken following informed consent, and was minimised on; (A) severity of LUT symptoms, as reported at study baseline by the International Prostate Symptom Score (I-PSS)(2) i.e., mild, moderate, or severe; and (B) status of anti-muscarinic medication, i.e., treatment naïve, failed or continuing treatment. 
Each participant attended one clinic visit in order to be clinically assessed, randomised and shown how to use the device. Participants who were allocated to the active phase were asked to place the self-adhesive surface electrode, 2cm behind the medial malleolus and the positive electrode 10cm proximal to it. The stimulation frequency was delivered at a fixed frequency of 10Hz and pulse width of 200µs in continuous mode.  Intensity of stimulation (range 0-50 mA) was guided by either a motor response flexion of the big toe) or sensory response (paraesthesia in the toes and sole). Those in the sham group applied the electrodes to the lateral side of the leg with a frequency of 2Hz and intensity of 2-4mA. Parameters were locked and duration of use recorded. All participants were asked to use the device for 30 minutes twice a week for 6 weeks. All participants received a weekly telephone call from the investigators to assess compliance
The trial had two co-primary outcome measures: ICIQ-UI-SF (3) (International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form) and the IPSS(2). These were completed at baseline, 6 and 12 weeks. A bladder frequency chart and resource questionnaire were also completed.  The participant experience and protocol fidelity were assessed at 6 weeks in a brief Exit Questionnaire and usage download from the stimulator. 
A sample size of 236 participants was deemed necessary to provide 90% power to detect a clinically important difference of 2.52 points on the ICIQ-UI-SF total score, based on a standard deviation (SD) of 5.5 and an attrition rate of 15%.  For the co-primary outcome measure, IPSS, a sample size of 234 was required based on the minimum clinically important difference of 3 points and a standard deviation of 6.5.  The analysis of primary and secondary outcomes compared randomised groups using linear mixed models adjusting for minimisation variables along with age, sex, and baseline values, with centre as a random effect.  Significance was set at the 5% level.  Cost-effectiveness analysis was conducted using the data collected from the resource use questionnaire combined with the the co-primary outcome measures.  Subgroup analyses were carried out by age, sex, medication status and symptom severity to test treatment interactions, at a stricter 1% significance level. The statistical analysis used an intention to treat approach
Results
242 participants were randomised (121 per arm), 59% of participants were male, the mean age was 69 years and mean time from diagnosis was 6 years. Questionnaire return rate was 79-90% at all time-points.
Attrition was low and similar in both groups. At 6 weeks, 8 had withdrawn, 4 were lost to follow-up and one had died. At 12 weeks there was one further withdrawal and 7 lost to follow-up. 
Tables 1 &2 : Primary Outcomes - shows that overall, there was no evidence of difference between the two groups on the ICIQ-UI SF score.  On the I-PSS score, for the Intervention Group, there was a statistically significant improvement of 2.5 at 6 weeks (Baseline score = 13.4 and Week 6 score = 10.9:(MD -1.49: 95% CI -2.72, -0.25; p=0.018)  ). 
The Bladder frequency data did not show any significant differences between the two groups.  The number of daily Micturition episodes were approximately 9 per day during all three phases.  The number of daily urgency episodes showed only small but not significant improvements over time as was the case with the number of daily leakage episodes. There was no difference in resource use between the two groups.
The participant experience of using the TTNS device was positive with 90% saying it was easy to use and 80% saying they were willing to continue using the device and would recommend it to others.  Compliance was high with averages of 5.6 and 5.8 hours of usage.  There were just 8 Adverse Events reported, none of which were related to the use of the device. There were no significant subgroup interactions.
Interpretation of results
A significant improvement was demonstrated in the total IPSS score at 6 weeks in favour of the intervention arm, though this fell short of the threshold for clinically meaningful improvement, defined as change of 3 points.  TTNS treatment was shown to be safe and associated with high compliance and willingness from patients to continue the treatment beyond the trial period.
Concluding message
In summary TTNS was demonstrated to be safe and may have provided slight  improvement in some urinary symptoms. However, the evidence  from this fully powered RCT is very limited to suggest that the TTNS intervention made a clinically significant improvement to urinary symptoms in People with Parkinson’s despite a high level of compliance in both groups.  We chose the  frequency and intensity suggested as optimal by previous research, however it is possible that another protocol might give different results and or accuracy of use may have been inadequate in such a population and should this could be investigated further.  The exceptional interest in people with Parkinson's in taking part in such a trial demonstrates an urgent need for robust interventions to address the LUT symptoms and improve their quality of life.
Figure 1 Table 1
Figure 2 Table 2
References
  1. Martinez-Martin, P, et al. Prevalence of nonmotor symptoms in Parkinson's disease in an international setting; study using nonmotor symptoms questionnaire in 545 patients. Mov Disord, 2007. 22(11): p. 1623-9
  2. Barry MJ, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? The Journal of Urology 1995. 154(5); 1770-1774
  3. Avery K., Donovan J., Peters T. et al,. ICIQ: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. Neurourol Urodyn., 2004. 23(4): p322-30
Disclosures
Funding Dunhill Medical ad Parkinson's UK Clinical Trial Yes Registration Number ISRCTN12437878 RCT Yes Subjects Human Ethics Committee East of Scotland Research Ethics Service (EoSRES), 18/ES00042, Helsinki Yes Informed Consent Yes
16/05/2022 04:10:36