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. Author manuscript; available in PMC: 2023 Apr 1.
Published in final edited form as: Am J Gastroenterol. 2022 Apr 1;117(4):654–667. doi: 10.14309/ajg.0000000000001605

Percutaneous tibial nerve stimulation vs sham for fecal incontinence in women: NeurOmodulaTion for Accidental Bowel Leakage Randomized Clinical Trial

Halina M Zyczynski 1, Holly E Richter 2, Vivian W Sung 3, Emily S Lukacz 4, Lily A Arya 5, David D Rahn 6, Anthony G Visco 7, Donna Mazloomdoost 8, Benjamin Carper 9, Marie G Gantz 9; NICHD Pelvic Floor Disorders Network
PMCID: PMC8988447  NIHMSID: NIHMS1763372  PMID: 35354778

Abstract

Objective:

To determine whether PTNS is superior to sham stimulation for treatment of fecal incontinence in women refractory to first-line treatments.

METHODS:

Women ≥18 years with ≥3 months of moderate to severe fecal incontinence that persisted after a 4-week run-in were randomized 2:1 (PTNS:Sham) to 12-weekly 30-minute sessions in this multicenter, single-masked, controlled superiority trial. The primary outcome was change from baseline fecal incontinence severity measured by St Mark’s score after 12 weeks treatment (range 0–24; minimal important difference, 3–5 points). Secondary outcomes included electronic bowel diary events and quality of life. Groups were compared using an adjusted general linear mixed model.

Results:

Of 199 women entering run-in, 166 (of 170 eligible) were randomized, (111 PTNS, 55 sham); mean (SD) age, 63.6 (11.6) years; baseline St. Mark’s score, 17.4 (2.7); recording 6.6 (5.5) fecal incontinence episodes per week. There was no difference in improvement from baseline St. Mark’s scores in the PTNS group compared to the sham group (−5.3 vs. −3.9 points, adjusted difference [95% confidence interval] −1.3 [−2.8, 0.2]). Groups did not differ in reduction in weekly fecal incontinence episodes (−2.1 vs. −1.9 episodes, adjusted difference [95% confidence interval] −0.26 [−1.85, 1.33]). Condition-specific QOL measures did not indicate a benefit of PTNS over sham. Serious adverse events occurred in 4% of each group.

Conclusions:

Though symptom reduction after 12 weeks of PTNS met a threshold of clinical importance it did not differ from sham. These data do not support use of PTNS as conducted, for treatment of fecal incontinence in women.

Keywords: Fecal incontinence, Accidental bowel leakage, Percutaneous tibial nerve stimulation, posterior tibial nerve stimulation, neuromodulation, sham electrical stimulation, randomized clinical trial

Introduction

Fecal incontinence (FI), also known as anal incontinence and accidental bowel leakage (ABL), is common; reported by 2% to 20% of community dwelling women1–3, 40% of whom report severe negative impact on quality of life. Effective, non-invasive therapies are limited4, 5. Neuromodulation has emerged as a promising third tier therapy. Sacral neuromodulation, approved for both urgency urinary incontinence and fecal incontinence, is safe and reversible but requires surgical intervention at substantial cost6. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive, office-based, low risk neuromodulation modality currently approved in the US for urgency urinary incontinence. Promising response rates of 63–82% in small, predominantly observational studies of FI7 have supported device marketing approval for FI in the European Union. The National Institute for Health and Care Excellence (NICE)8 includes PTNS among treatment options for FI though acknowledges the need for further research to inform to efficacy and target populations. A multicenter pragmatic, randomized trial of PTNS versus sham reported no group difference in a diary-based primary outcome of ≥50% reduction in weekly FI episodes9 though PTNS did result in significantly greater reduction in total weekly FI and urgency associated FI episodes. Posthoc analyses excluding subjects with obstructed defecation symptoms, a subset known to be refractory to FI therapy10 found a significant clinical effect of PTNS11. These findings support the need for additional controlled efficacy trials of PTNS in a well characterized population.

The aim of this randomized clinical trial was to determine if 12 weeks of treatment with PTNS is more effective than sham stimulation in reducing FI severity, as measured by change from baseline in St. Mark’s score, in women refractory to first-line therapies. Secondary aims included comparing changes from baseline in bowel diary measures, self-reported functional outcomes, and quality of life.

METHODS

Study Design and Oversight

This was a multicenter, single-masked, randomized, superiority trial conducted at 9 US clinical sites of the National Institutes of Health Pelvic Floor Disorders Network under approval of a Data and Safety Monitoring Board and the University of Pittsburgh institutional review board (NCT 03278613). All participants provided written informed consent. Study methods have been published12, and the protocol and statistical analysis plan appear in supplementary materials. Enrollment began February 9, 2018, and follow-up closed March 9, 2020 upon analysis of data from all subjects who completed initial treatment in the randomized trial (Part 1). (Supplemental Digital Content Figure 1. Study Flow Diagram)

Participants

Women ≥18 years with moderate to severe ABL symptoms for ≥3 months, defined as a baseline St. Mark’s score ≥12 points, and inadequate symptom control from supervised pelvic muscle training and constipating medications, were eligible to enroll into a 4-week run-in. Women were excluded for self-report of uncontrolled diarrhea or severe constipation as the predominant stool type in the preceding 3 months based on Bristol stool scale,13 anatomic compromise of the anus or rectum (unrepaired rectovaginal fistula or 4th degree obstetrical laceration, rectal prolapse, congenital anorectal malformation, colon resection), and known contraindications for PTNS.12

Intervention

The study included a 4-week run-in prior to randomization to 12 weekly stimulation sessions (Part 1). Treatment responders defined as those reporting ≥4-point reduction in St. Mark’s score underwent a second randomization to ‘as needed’ or scheduled maintenance sessions (Part 2) for an additional 9 months beyond treatment initiation. The protocol specified that if Part 1 did not demonstrate superiority of PTNS over sham, Part 2 would be discontinued.

During the run-in, participants received standardized verbal and written information on causes and treatments for FI including dietary and lifestyle modifications14. They also completed two 7-day bowel diaries in weeks 1 and 4. Women were eligible for randomization to Part 1 if they provided two complete diaries (defined as having recorded events on ≥10 of 14 days with minimum of 3 consecutive days per week) and reported a St. Mark’s score of ≥12 points at the end of the run-in.

Part 1 randomization assignment was 2:1 PTNS:sham, using randomly permuted blocks, stratified by site and type of run-in diary completed (eDiary or paper). Stimulation was delivered to a single lower extremity in 12 weekly 30-minute sessions. PTNS employed the ES-130 pulse generator (ITO, Tokyo, Japan) programed to be consistent with the Stoller Afferent Nerve Stimulator (SANS) (UroSurge, Coralville, Iowa, USA), (US Patent No.: US 6,493,588) to deliver a threshold current to a needle electrode to induce toe twitch and, or sensation15, 16. The validated sham intervention employed a Streitberger retractable placebo acupuncture needle and surface electrodes positioned on the top and bottom of the fifth metatarsal, each connected to a transcutaneous electrical nerve stimulator (TENS) that created a sensory effect without delivering a therapeutic effect17. Procedures are detailed in the protocol (Supplementary material) and methods paper 12. Adherence to the study protocol was defined as completing 10 of 12 sessions within a 14-week window.

Outcome Measures

The primary outcome was change from baseline St. Mark’s Score measured after 12 weekly treatments. The St. Mark’s Score is a 7 item, validated patient-reported outcome (PRO).18–20 Higher scores (range 0–24 points) indicate greater symptom severity, and the minimal important difference (MID) is 3–5 points20. The St. Mark’s Score was assessed at baseline, and after the 4th, 8th, and 12th weekly session.

Secondary outcomes included bowel movement and stool leakage episodes per week qualified by urgency and stool consistency recorded for 14-days on the PFDN Bowel eDiary phone application21 at baseline, and with start dates at the 6th and 12th stimulation session. In the absence of a single superior measure for ABL, a robust panel of PRO measures were collected assessing FI symptom severity, quality of life,22, 23 co-existent bowel and bladder symptoms,24 constipation symptoms,25 global impression of improvement, behavior adaptations for pelvic floor disorders26 and sexual function27. The Patient Global Symptom Control rating20, and adverse events were ascertained at each treatment visit.

Statistical Analysis

Assuming a two-sided alpha of 0.05 and standard deviation (SD) of 728, using a 2:1 treatment allocation, 147 women provided 90% power to detect a between-group difference of 4 points in mean change from baseline in St. Mark’s scores after 12 weeks of stimulation. After adjusting for 10% dropout, 165 (PTNS=110, Sham=55) was the target sample size for Part 1.

Baseline characteristics were compared between groups using Student’s t tests for continuous variables and chi-square tests for categorical variables. The primary analysis used an intention-to-treat approach, and models included all eligible, randomized participants with outcome data at one or more time points. A general linear mixed model estimated the change from baseline in St. Mark’s Score across all time points through 12 weeks of treatment. Treatment group, time as a linear and quadratic effect, the stratification factor of site, and interactions between treatment group and time were included as fixed effects. The correlation between repeated measures on the same participant was modeled using an auto-regressive covariance structure. The model-estimated change from baseline in St. Mark’s score after 12 treatments was compared between groups using a two-sided test at an alpha level of 0.05. In a sensitivity analysis, multiple imputation was used to estimate missing values.

A per-protocol analysis included participants who attended at least 10 of 12 stimulation sessions. Other secondary outcomes were analyzed using similar methods to the primary analysis for continuous variables, or analogous generalized linear mixed models for categorical outcomes. No alpha adjustments were made for evaluation of multiple outcomes. Analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Inc., Cary, North Carolina).

RESULTS

Study Population

Between February 9, 2018 and September 24, 2019, 199 women entered the run-in, 166 of 170 eligible participants were randomized (111 PTNS vs. 55 sham) (Figure 1). Table 1 presents baseline sociodemographic and clinical characteristics. Overall, participants were 63.6 (±11.6) years old, predominantly White (80.7%), and overweight or obese (76.2%). The run-in resulted in modest improvement in symptom severity with mean change in St. Mark’s Scores −0.54 (±2.75). Prior to randomization, participants reported 13.3 (±7.3) bowel movements and 6.6 (±5.5) leaks per week, of which half were associated with urgency.

Figure 1.

Figure 1

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NOTABLe Trial CONSORT Diagram

TABLE 1.

Baseline Characteristics of Eligible and Randomized Patients in Part 1.

Treatment Group
Characteristic Category Total (N=166) PTNS (N=111) Sham (N=55)
Age, mean (SD), y 63.6 (11.6) 63.5 (11.9) 63.8 (11.2)
Race, n/N (%) American Indian/Alaska Native 2/166 (1.2) 1/111 (0.9) 1/55 (1.8)
Asian 2/166 (1.2) 1/111 (0.9) 1/55 (1.8)
Black or African American 19/166 (11.4) 10/111 (9.0) 9/55 (16.4)
Native Hawaiian/Pacific Islander 2/166 (1.2) 1/111 (0.9) 1/55 (1.8)
White 134/166 (80.7) 95/111 (85.6) 39/55 (70.9)
Unknown/Not Reported 7/166 (4.2) 3/111 (2.7) 4/55 (7.3)
Ethnicity, n/N (%) Hispanic/Latina 16/166 (9.6) 10/111 (9.0) 6/55 (10.9)
Not Hispanic/Latina 148/166 (89.2) 99/111 (89.2) 49/55 (89.1)
Unknown/Not Reported 2/166 (1.2) 2/111 (1.8) 0/ (0.0)
Primary language, n/N (%) English 160/166 (96.4) 107/111 (96.4) 53/55 (96.4)
Spanish 6/166 (3.6) 4/111 (3.6) 2/55 (3.6)
Education, n/N (%) Some college or greater 115/166 (69.3) 78/111 (70.3) 37/55 (67.3)
No college education 51/166 (30.7) 33/111 (29.7) 18/55 (32.7)
Insurance status, n/N (%) Private/HMO 59/166 (35.5) 42/111 (37.8) 17/55 (30.9)
Medicare/Medicaid 46/166 (27.7) 28/111 (25.2) 18/55 (32.7)
Private and Medicare/Medicaid 42/166 (25.3) 28/111 (25.2) 14/55 (25.5)
Other/None 19/166 (11.4) 13/111 (11.7) 6/55 (10.9)
Body Mass Index, mean (SD), kg/m2 29.4 (6.6) 29.2 (6.9) 29.7 (6.0)
Body Mass Index, n/N (%) <25 kg/m2 39/164 (23.8) 28/110 (25.5) 11/54 (20.4)
25 – 29.9 kg/m2 55/164 (33.5) 39/110 (35.5) 16/54 (29.6)
>= 30 kg/m2 70/164 (42.7) 43/110 (39.1) 27/54 (50.0)
Anal sphincter squeeze, n/N (%) 146/164 (89.0) 99/110 (90.0) 47/54 (87.0)
Any vaginal deliveries, n/N (%) 146/166 (88.0) 98/111 (88.3) 48/55 (87.3)
Any cesarean deliveries, n/N (%) 19/166 (11.4) 16/111 (14.4) 3/55 (5.5)
Menopausal status, n/N (%) Pre-menopausal 15/166 (9.0) 11/111 (9.9) 4/55 (7.3)
Post-menopausal 141/166 (84.9) 92/111 (82.9) 49/55 (89.1)
Not sure 10/166 (6.0) 8/111 (7.2) 2/55 (3.6)
Currently using estrogen, n/N (%) 46/166 (27.7) 28/111 (25.2) 18/55 (32.7)
Current smoker, n/N (%) 14/166 (8.4) 9/111 (8.1) 5/55 (9.1)
Prior fecal incontinence surgery, n/N (%) 8/166 (4.8) 6/111 (5.4) 2/55 (3.6)
Prior anal/rectal surgery, n/N (%) 28/166 (16.9) 21/111 (18.9) 7/55 (12.7)
Prior urinary incontinence surgery, n/N (%) 40/166 (24.1) 26/111 (23.4) 14/55 (25.5)
Prior prolapse surgery, n/N (%) 40/166 (24.1) 22/111 (19.8) 18/55 (32.7)
Hysterectomy, n/N (%) 75/166 (45.2) 48/111 (43.2) 27/55 (49.1)
Taking fiber supplements, n/N (%) 66/160 (41.3) 51/108 (47.2) 15/52 (28.8)
Dietary fiber intake, mean (SD), g 13.8 (4.2) 13.9 (4.1) 13.7 (4.3)
Bristol Stool Type, n/N (%) Type 2 - Sausage-shaped but lumpy 13/166 (7.8) 10/111 (9.0) 3/55 (5.5)
Type 3 - Like a sausage but with cracks on its surface 23/166 (13.9) 16/111 (14.4) 7/55 (12.7)
Type 4 - Like a sausage or snake, smooth and soft 42/166 (25.3) 24/111 (21.6) 18/55 (32.7)
Type 5 - Soft blobs with clear-cut edges 34/166 (20.5) 23/111 (20.7) 11/55 (20.0)
Type 6 - Fluffy pieces with ragged edges, a mushy stool 54/166 (32.5) 38/111 (34.2) 16/55 (29.1)
Pain/discomfort in abdomen in last 3 months, n/N (%)
Less than once per week 102/166 (61.4) 61/111 (55.0) 41/55 (74.5)
At least once per week 64/166 (38.6) 50/111 (45.0) 14/55 (25.5)
Pain/discomfort ≥6 months, n/N (%) 82/166 (49.4) 58/111 (52.3) 24/55 (43.6)
Diagnosed with Irritable Bowel Syndrome, n/N (%) 35/166 (21.1) 25/111 (22.5) 10/55 (18.2)
Frequency of loose/mushy/ watery stools in last 3 months, n/N (%)
Never or rare 57/166 (34.3) 32/111 (28.8) 25/55 (45.5)
Sometimes 34/166 (20.5) 28/111 (25.2) 6/55 (10.9)
Often/most of the time/always 75/166 (45.2) 51/111 (45.9) 24/55 (43.6)
Bowel movements per week, mean (SD), No. 13.3 (7.3) 13.6 (7.6) 12.7 (6.8)
Bowel movements with urgency per week, mean (SD), No. 6.8 (6.0) 7.3 (6.2) 5.9 (5.5)
Accident-free days per week, mean (SD), No. 3.4 (2.0) 3.3 (1.9) 3.6 (2.1)
Leaks per week, mean (SD), No. 6.6 (5.5) 6.8 (5.2) 6.3 (6.2)
Leaks with urgency per week, mean (SD), No. 3.4 (4.1) 3.6 (4.2) 2.9 (4.0)
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Abbreviations:

PTNS, Percutaneous tibial nerve stimulation; SD, standard deviation.

Primary Outcome

The unadjusted mean St. Mark’s Score for the PTNS group at baseline was 17.5 (±2.5) and after 12 weeks was 12.2 (±5.0), for an adjusted mean change of −5.3 points (95% confidence interval [CI], −6.2, −4.3) vs sham group unadjusted mean scores of 17.3 (±3.0) at baseline and 13.3 (±4.7) points after 12 weeks, for an adjusted mean change of −3.9 points (95% CI, −5.2, −2.7) (Table 2). There was no significant difference between groups in improvement of St. Mark’s scores (adjusted difference −1.3, 95% CI,−2.8, 0.2). Responders to treatment were 64/104 (61.5%) assigned to PTNS and 26/54 (48.1%) of sham subjects (unadjusted OR 1.71, 95% CI 0.86, 3.39; p=0.12). Sensitivity and protocol analyses were consistent with the primary analysis. The observed divergence in total St. Mark’s scores after 8 weeks (Figure 2) is largely due to a significantly lower proportion of PTNS subjects reporting daily or weekly of solid stool leakage and less use of protection with pads or plugs compared to sham (Table 3).

Table 2.

Fecal incontinence, pelvic symptoms, and secondary functional outcomes from baseline through 12 weeks of stimulation sessions (ITT)a

Baselineb 4 Weeksb 8 Weeksb 12 Weeksb
Outcome Type PTNS (N=111) Sham (N=55) PTNS (N=102) Sham (N=50) PTNS (N=105) Sham (N=52) PTNS (N=104) Sham (N=54)
St. Mark’s Score c
Score, unadjusted mean (SD) 17.5 (2.5) 17.3 (3.0) 14.6 (4.2) 13.9 (5.0) 13.2 (4.9) 13.2 (4.8) 12.2 (5.0) 13.3 (4.7)
Difference from baseline, adjusted mean (95% CI) −2.7 (−3.7, −1.8) −3.3 (−4.7, −2.0) −4.2 (−5.1, −3.3) −4.2 (−5.4, −2.9) −5.3 (−6.2, −4.3) −3.9 (−5.2, −2.7)
Difference in difference, adjusted mean (95% CI) 0.62 (−0.94, 2.18) −0.02 (−1.56, 1.51) −1.31 (−2.84, 0.22)
P-value p=0.43 p=0.98 p=0.09
Fecal Incontinence Episodes per Week
Score, unadjusted mean (SD) 6.8 (5.2) 6.3 (6.2) 4.4 (4.5) 4.3 (5.3) 4.1 (5.3) 4.1 (5.1)
Difference from baseline, adjusted mean (95% CI) −2.2 (−3.2, −1.2) −1.5 (−2.8, −0.1) −2.1 (−3.1, −1.2) −1.9 (−3.2, −0.5)
Difference in difference, adjusted mean (95% CI) −0.69 (−2.27, 0.90) −0.26 (−1.85, 1.33)
P-value p=0.39 p=0.75
Urgency Fecal Incontinence Episodes per Week
Score, unadjusted mean (SD) 3.6 (4.2) 2.9 (4.0) 2.3 (2.7) 2.0 (3.2) 2.3 (3.5) 2.0 (3.5)
Difference from baseline, adjusted mean (95% CI) −1.1 (−1.6, −0.6) −0.3 (−1.0, 0.4) −1.0 (−1.5, −0.5) −0.6 (−1.3, 0.1)
Difference in difference, adjusted mean (95% CI) −0.82 (−1.66, 0.01) −0.40 (−1.24, 0.44)
P-value p=0.05 p=0.35
Bowel Movements per Week
Score, unadjusted mean (SD) 13.6 (7.6) 12.7 (6.8) 12.0 (5.7) 12.5 (8.8) 11.5 (5.4) 11.1 (6.2)
Difference from baseline, adjusted mean (95% CI) −1.4 (−2.5, −0.3) −0.1 (−1.6, 1.4) −1.6 (−2.7, −0.5) −1.2 (−2.7, 0.3)
Difference in difference, adjusted mean (95% CI) −1.29 (−3.05, 0.47) −0.43 (−2.20, 1.34)
P-value p=0.15 p=0.63
Urgency Bowel Movements per Week
Score, unadjusted mean (SD) 7.3 (6.2) 5.9 (5.5) 5.6 (5.2) 4.5 (5.2) 4.8 (4.6) 3.7 (4.8)
Difference from baseline, adjusted mean (95% CI) −1.3 (−2.3, −0.4) −0.9 (−2.2, 0.4) −2.0 (−2.9, −1.0) −1.7 (−3.1, −0.4)
Difference in difference, adjusted mean (95% CI) −0.47 (−2.01, 1.07) −0.21 (−1.76, 1.34)
P-value p=0.55 p=0.79
Fecal Incontinence Episode-Free Days per Week
Score, unadjusted mean (SD) 3.3 (1.9) 3.6 (2.1) 4.4 (1.9) 4.5 (1.7) 4.7 (2.1) 4.5 (2.1)
Difference from baseline, adjusted mean (95% CI) 1.0 (0.5, 1.4) 0.8 (0.2, 1.3) 1.2 (0.8, 1.6) 0.8 (0.2, 1.4)
Difference in difference, adjusted mean (95% CI) 0.18 (−0.48, 0.85) 0.39 (−0.28, 1.06)
P-value p=0.59 p=0.26
ABLe Overall Score d
Score, unadjusted mean (SD) 2.9 (0.5) 2.7 (0.5) 2.6 (0.5) 2.5 (0.6) 2.4 (0.6) 2.3 (0.6)
Difference from baseline, adjusted mean (95% CI) −0.3 (−0.4, −0.1) −0.2 (−0.4, 0.0) −0.5 (−0.6, −0.4) −0.3 (−0.5, −0.2)
Difference in difference, adjusted mean (95% CI) −0.05 (−0.25, 0.15) −0.16 (−0.36, 0.04)
P-value p=0.63 p=0.12
FISI Patient Score e
Score, unadjusted mean (SD) 32.2 (8.3) 33.1 (10.7) 26.8 (10.5) 27.2 (11.1) 24.2 (9.9) 26.5 (11.6)
Difference from baseline, adjusted mean (95% CI) −4.0 (−6.2, −1.7) −5.0 (−8.0, −1.9) −6.5 (−8.7, −4.2) −5.9 (−8.9, −2.9)
Difference in difference, adjusted mean (95% CI) 0.99 (−2.62, 4.61) −0.59 (−4.20, 3.02)
P-value p=0.59 p=0.75
FISI Doctor Score e
Score, unadjusted mean (SD) 34.5 (8.2) 35.5 (9.8) 29.0 (10.8) 29.2 (11.4) 26.5 (10.9) 28.6 (12.2)
Difference from baseline, adjusted mean (95% CI) −3.9 (−6.3, −1.6) −5.4 (−8.6, −2.2) −6.3 (−8.7, −3.9) −6.2 (−9.3, −3.1)
Difference in difference, adjusted mean (95% CI) 1.45 (−2.33, 5.23) −0.10 (−3.87, 3.68)
P-value p=0.45 p=0.96
PFDI Score f
Score, unadjusted mean (SD) 111.7 (50.2) 115.6 (60.0) 94.4 (47.5) 88.8 (54.7) 83.9 (51.2) 78.8 (49.9)
Difference from baseline, adjusted mean (95% CI) −15.1 (−24.0, −6.3) −26.2 (−38.4, −13.9) −25.9 (−34.8, −16.9) −36.3 (−48.3, −24.3)
Difference in difference, adjusted mean (95% CI) 11.01 (−3.47, 25.49) 10.47 (−3.87, 24.81)
P-value p=0.14 p=0.15
UDI Score g
Score, unadjusted mean (SD) 38.7 (26.9) 42.2 (29.6) 34.9 (27.2) 29.7 (26.5) 30.3 (28.0) 27.7 (24.1)
Difference from baseline, adjusted mean (95% CI) −2.6 (−6.9, 1.7) −11.5 (−17.4, −5.5) −7.3 (−11.6, −2.9) −14.3 (−20.2, −8.5)
Difference in difference, adjusted mean (95% CI) 8.89 (1.81, 15.97) 7.03 (0.02, 14.04)
P-value p=0.01 p=0.05
POPDI Score g
Score, unadjusted mean (SD) 24.4 (19.3) 25.2 (22.1) 19.3 (15.5) 20.1 (18.7) 16.8 (16.4) 15.1 (16.4)
Difference from baseline, adjusted mean (95% CI) −4.0 (−7.4, −0.6) −4.7 (−9.3, 0.0) −6.5 (−9.9, −3.1) −9.5 (−14.0, −4.9)
Difference in difference, adjusted mean (95% CI) 0.66 (−4.84, 6.17) 2.95 (−2.50, 8.41)
P-value p=0.81 p=0.29
CRADI Score g
Score, unadjusted mean (SD) 48.6 (17.4) 48.3 (19.1) 40.2 (17.1) 39.0 (19.9) 36.8 (18.6) 35.9 (20.2)
Difference from baseline, adjusted mean (95% CI) −8.6 (−12.6, −4.5) −10.1 (−15.7, −4.4) −12.1 (−16.2, −8.0) −12.6 (−18.1, −7.0)
Difference in difference, adjusted mean (95% CI) 1.50 (−5.17, 8.16) 0.50 (−6.11, 7.10)
P-value p=0.66 p=0.88
PFIQ Score h
Score, unadjusted mean (SD) 95.7 (59.9) 87.5 (58.5) 73.9 (54.6) 59.6 (45.2) 62.0 (51.9) 56.5 (46.9)
Difference from baseline, adjusted mean (95% CI) −17.9 (−27.1, −8.7) −27.4 (−40.0, −14.7) −30.9 (−40.2, −21.7) −30.1 (−42.5, −17.7)
Difference in difference, adjusted mean (95% CI) 9.49 (−5.50, 24.48) −0.83 (−15.68, 14.02)
P-value p=0.21 p=0.91
UIQ Score i
Score, unadjusted mean (SD) 28.1 (27.1) 27.3 (27.5) 23.5 (24.1) 17.2 (20.5) 19.7 (23.6) 16.5 (21.4)
Difference from baseline, adjusted mean (95% CI) −2.8 (−6.5, 0.9) −9.4 (−14.6, −4.3) −7.0 (−10.7, −3.2) −10.2 (−15.2, −5.1)
Difference in difference, adjusted mean (95% CI) 6.65 (0.57, 12.73) 3.20 (−2.82, 9.21)
P-value p=0.03 p=0.30
POPIQ Score i
Score, unadjusted mean (SD) 13.7 (20.9) 10.5 (19.3) 9.5 (16.8) 5.3 (13.2) 7.5 (15.1) 5.1 (11.9)
Difference from baseline, adjusted mean (95% CI) −3.7 (−7.1, −0.2) −6.0 (−10.8, −1.3) −5.9 (−9.4, −2.4) −6.1 (−10.8, −1.4)
Difference in difference, adjusted mean (95% CI) 2.39 (−3.25, 8.04) 0.18 (−5.41, 5.78)
P-value p=0.41 p=0.95
CRAIQ Score i
Score, unadjusted mean (SD) 53.9 (29.3) 49.7 (28.3) 40.9 (26.5) 37.0 (26.7) 34.8 (26.3) 34.9 (27.9)
Difference from baseline, adjusted mean (95% CI) −11.4 (−16.5, −6.2) −11.9 (−19.0, −4.9) −18.0 (−23.2, −12.8) −13.8 (−20.8, −6.9)
Difference in difference, adjusted mean (95% CI) 0.55 (−7.82, 8.93) −4.20 (−12.52, 4.12)
P-value p=0.90 p=0.32
ABI Hygiene Score j
Score, unadjusted mean (SD) 53.9 (20.2) 54.7 (21.6) 44.5 (23.8) 51.4 (24.0)
Difference from baseline, adjusted mean (95% CI) −10.0 (−14.1, −5.8) −2.9 (−8.3, 2.6)
Difference in difference, adjusted mean (95% CI) −7.08 (−13.59, −0.56)
P-value p=0.03
ABI Avoidance Score j
Score, unadjusted mean (SD) 41.6 (21.7) 38.8 (24.0) 29.7 (22.2) 32.2 (24.7)
Difference from baseline, adjusted mean (95% CI) −12.4 (−16.4, −8.4) −6.0 (−11.2, −0.7)
Difference in difference, adjusted mean (95% CI) −6.39 (−12.64, −0.14)
P-value p=0.05
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Abbreviations:

ABLe, Accidental Bowel Leakage Symptom (ABLe) Questionnaire; FISI, Fecal Incontinence Severity Index; PFDI, Pelvic Floor Distress Inventory; UDI, Urogenital Distress Inventory; POPDI, Pelvic Organ Prolapse Distress Inventory; CRADI, Colorectal-Anal Distress Inventory; PFIQ, Pelvic Floor Impact Questionnaire; UIQ, Urinary Impact Questionnaire; POPIQ, Pelvic Organ Prolapse Impact Questionnaire; CRAIQ, Colorectal-Anal Impact questionnaire; ABI, Adaptive Behavior Index.

a

Difference from baseline, difference in difference, and P-values are derived from longitudinal treatment models that accounted for multiple observations per participant and were adjusted for time since baseline, interaction between treatment and time and clinical site.

b

Sample sizes present the number of participants with observed data at each time point.

c

The St. Mark’s score ranges from 0 to 24; the minimum clinically important difference (MCID) is 3 to 5 points, with higher scores indicating greater symptom severity.

d

The ABLe overall score ranges from 0 to 4 with higher scores indicating greater condition severity.

e

The FISI patient score ranges from 0 to 61 and the FISI doctor score ranges from 0 to 57 with higher scores indicating greater symptom severity.

f

The PFDI total score ranges from 0 to 300 with higher scores indicating greater distress.

g

The PFDI subscale scores range from 0 to 100 with higher scores indicating greater distress.

h

The PFIQ total score ranges from 0 to 300 with higher scores indicating greater negative impact.

i

The PFIQ subscale scores range from 0 to 100 with higher scores indicating greater negative impact.

j

The ABI hygiene and avoidance scores range from 0 to 100 with higher scores indicating greater need for adaptive behaviors.

Figure 2.

Figure 2

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NOTABLe Change from baseline St. Mark’s Score

Table 3.

Additional Secondary Outcomes after 12 weeks of stimulation sessions (ITT)

PTNS Sham
Outcome Type N n (%) N n (%) Odds Ratio, 95% CI P-value
Responders to Treatment 104 64 (61.5) 54 26 (48.1) 1.71 (0.86, 3.39) 0.12
50% Improvement in Fecal Incontinence Episodes/Week 97 51 (52.6) 48 19 (39.6) 1.70 (0.81, 3.56) 0.16
75% Improvement in Fecal Incontinence Episodes/Week 97 32 (33.0) 48 13 (27.1) 1.36 (0.59, 3.14) 0.46
Patient Global Impression of Improvement 103 47 (45.6) 54 21 (38.9) 1.31 (0.66, 2.59) 0.44
Patient Global Symptom Control 104 82 (78.8) 54 40 (74.1) 1.47 (0.65, 3.34) 0.35
St. Mark’s (Vaizey) Questions a
Incontinence for solid stool (weekly or daily) 104 21 (20.2) 54 19 (35.2) 0.47 (0.22, 0.97) 0.05
Incontinence for liquid stool (weekly or daily) 104 29 (27.9) 54 19 (35.2) 0.71 (0.35, 1.44) 0.37
Incontinence for gas (weekly or daily) 104 54 (51.9) 54 26 (48.1) 1.16 (0.60, 2.25) 0.74
Frequency of altered lifestyle (weekly or daily) 104 33 (31.7) 54 20 (37.0) 0.79 (0.40, 1.57) 0.59
Pad/plug use 104 66 (63.5) 54 43 (79.6) 0.44 (0.21, 0.96) 0.05
Taking constipating medicines 104 36 (34.6) 54 18 (33.3) 1.06 (0.53, 2.12) >0.99
Inability to defer defecation for 15 minutes 104 63 (60.6) 54 36 (66.7) 0.77 (0.39, 1.53) 0.49
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Abbreviations:

ITT, Intent-to-Treat; PTNS, Percutaneous tibial nerve stimulation; SD, standard deviation.

a

Odds ratios and p-values for individual St. Mark’s (Vaizey) questionnaire items are unadjusted.

Secondary Outcomes

Prespecified secondary and exploratory outcomes are reported in Tables 2 and 3. Weekly frequency of diary-documented bowel events and fecal incontinence episode-free days did not differ between groups. Approximately half of participants reported ≥50% reduction in weekly FI episodes, and a third had a ≥ 75%reduction, without meaningful differences between groups. Furthermore, both groups reported high levels of symptom control 79% (PTNS) versus 74% (Sham) with no group difference in perceived improvement (Table 3). Significant group differences were noted in adaptive behaviors, with the PTNS group reporting greater decreases from baseline in the hygiene and avoidance-related activities domains of the ABI (Table 2). Group differences in condition-specific QOL measures varied. Compared to sham, the PTNS group reported significantly greater improvement in three of four subscales of the FIQL for the Lifestyle, Depression/ Self-perception, and Embarrassment scores [Supplemental Digital Content Table 1]. Most other QOL measures did not indicate group differences.

Both groups demonstrated high adherence to the treatment schedule (99/111 (89.2%) PTNS, 51/55 (92.7%) sham). Validity of the sham was assessed at the close of Part 1: 61/103 (59.2%) of PTNS and 32/54 (59.3%) of the sham group reported not knowing their group assignment. Of those who guessed, 29/42 (69%) assigned to PTNS, and 10/22 (45.5%) in the sham group were correct. Interventionists recorded sensory, motor or both responses to PTNS in 97.5%, 31.8%, and 29.7% of sessions. New non-pharmacologic treatment for ABL was initiated by 5 PTNS and 3 sham participants with an additional 9 PTNS and 2 sham subjects starting new medication for ABL. The proportion of participants taking constipating medications was similar between groups at the end of Part 1.

Adverse events are summarized by classification [Supplemental Digital Content Table 2] and by system organ class [Supplemental Digital Content Table 3]. Paresthesia was reported in 11 (10%) of PTNS and 2 (4%) of the sham group. Bleeding (8%) and pain (2%) at the needle insertion site were exclusively reported in the PTNS group. Six participants experienced serious adverse events, 4 (4%) in the PTNS group and 2 (4%) in the sham group; none were treatment related.

Discussion

In this randomized controlled trial of women with refractory FI, PTNS and sham stimulation did not differ in their impact on symptom severity, incontinence events or most quality of life measures after 12 weekly sessions. Both groups experienced significant, clinically important reductions in patient-reported symptoms, weekly frequency of FI episodes compared to baseline, and compelling symptom control of 74 –78%, highlighting the importance of a sham arm when investigating therapeutic interventions for functional bowel disorders, in which placebo effects approximate 40%29, 30 There were, however, secondary outcomes including the Fecal Incontinence Quality of Life and Adaptive Behaviors Index which favored PTNS over sham. Nonetheless, group differences were modest, and overall, the findings of this study do not support the broad use of this PTNS protocol as standard FI therapy.

This study was conducted to address conflicting evidence on the efficacy of PTNS for treatment of ABL and the need for confirmatory Level I evidence prior to clinical adoption of this therapy in the United States. Near the end of protocol development, Knowles and colleagues published the largest, most rigorous evaluation of PTNS for the treatment of FI, in 227 women and men recruited from colorectal surgery clinics in the United Kingdom. Similar to NOTABLe, the CONFIDeNT trial found no significant treatment response in active PTNS treatment compared to sham for the primary outcome of ≥50% reduction in weekly FI episodes, conditional and related pelvic symptom quality of life measures and patient global impression of improvement.9 The NOTABLe trial addresses some of the limitations of CONFIDeNT and distinguishes itself for its objective eligibility criteria of a study population with moderate to severe symptom burden in the absence of extremes of stool consistency; collection of bowel events with an electronic bowel diary to manage concerns of veracity of diary data; a run-in phase to address the potential therapeutic effect of journaling; selection of a comprehensive primary outcome which accounts for elements of frequency, severity, volume, bother, and desire for treatment, and use of a validated sham stimulation.

NOTABLe findings generally align with those of the CONFIDeNT trial; however, there are important differences in the population studied and design of the trial which lend confidence and generalizability to the combined conclusions. The populations had similar baseline frequency of incontinence episodes (6–7/week) with half associated with urgency and similar baseline fecal incontinence quality of life scores. However, the NOTABLe trial exclusively enrolled women, recruited from the community through advertising and from urogynecology clinics compared to colorectal specialty clinics. They were slightly older (by 6 years), more symptomatic based on St. Mark’s score (17 vs. 15 points), and less likely to report prior ano/rectal surgery for FI than those enrolled in the CONFIDeNT trial. The difference in population, diary modality or inclusion of run-in in the current study may account for the differences in results between these studies. The UK study found significantly greater improvement in diary documented FI episodes/week compared to sham, but not in any of the FI quality of life domains. In contrast, the women in the current study had no group difference in reduction of incontinence episodes but did report greater improvements with PTNS compared to sham in lifestyle, depression, and embarrassment domains of the Rockwood FIQL questionnaire. Additionally, at the end of Part 1, the PTNS group reported less use of adaptive behaviors to manage their ABL symptoms which may reflect improved confidence in their ability to be continent despite unchanged symptom severity.

Despite deliberate, pre-randomization interventions intended to isolate the effects of education, lifestyle modifications and journaling in diaries, the sham stimulation group reported statistically significant reductions in St. Mark’s Score of 3.9 points, within the MID range of 3–5 points leading to a non-significant difference between groups. The placebo effect noted in this trial is similar to that noted by this same research network in a 2×2 factorial designed trial comparing first line FI interventions: oral placebo to loperamide, and anal sphincter exercise training with biofeedback to an educational pamphlet.28 Participants assigned to oral placebo and educational materials reported reductions in St. Mark’s Scores of 3.4 at 12 weeks and 4.5 at 24 weeks. A systematic review of sham PTNS stimulation techniques in FI and constipation studies found variations in needle insertion and activation of nerve stimulators31. In the absence of a gold standard, this study employed a validated sham stimulation technique for PTNS studies of overactive bladder syndrome.32 Despite the run-in and proven sham technique, the symptom reduction reported by the sham group was significant and consistent with the literature28–31. Though the underlying mechanism for sham effects is unknown, proposed theories include natural variation in symptoms, regression to the mean, and psychological and neurobiological effects31, 33–36. Future analyses are planned to identify predictors of the sham response as well as potential genetic contributions to this phenomenon in this cohort of women.

The protocol choice of a generic electrical stimulation device in lieu of more costly proprietary devices for PTNS lends generalizability to study findings and accessibility of this therapy globally. The technique elicited the desired sensory and/or motor response in over 97% of sessions with outcomes comparable to other trials using marketed devices FDA-approved for urgency urinary incontinence (Cogentix/Uroplasty, Medtronic). While possible, it is unlikely that results of this trial would be different with use of an alternate pulse generators as FDA approvals of PTNS stimulators have been predicated on equivalence to the SANS unit. Consistent with other PTNS trials, adverse events were infrequent, mostly mild, and similar across treatment groups with no treatment-related serious adverse events.

Trial strengths include its rigorous study design with run-in and eligibility criteria that aided in enrollment of participants with moderate to severe symptoms less likely to spontaneously resolve with time or diary prompted dietary and behavioral modifications. The validated sham effectively maintained masking, likely contributing to the high adherence to treatment schedules in both groups.

Our findings are limited to females, many seeking care for pelvic floor disorders at urogynecology clinics, and to the protocol specified frequency and duration of PTNS sessions. Results should not be extrapolated to men who are equally affected by FI1. The absence of a ‘no treatment’ control arm, prevents us from quantifying the effect of the sham. Despite exclusion of women who regularly experienced watery diarrhea (Bristol stool 7), a substantial number of subjects reported symptoms of irritable bowel syndrome, with 75/166 (45.2%) reporting loose/mushy/watery stools, often/most of the time/always in the last 3 months. Though participants were not characterized with anorectal imaging or functional testing, a secondary analysis is planned to identify predictors of clinically meaningful response including stool frequency, consistency, and symptoms attributed to obstructive defecation. Lastly, the primary endpoint after 12 weekly, 30-minute treatment sessions was empirically adopted from OAB studies of PTNS. Continuation of assigned stimulation sessions in the maintenance phase (Part 2) will enable exploratory analyses of longer treatment exposure in both groups.

In conclusion, the study findings do not support the general use of PTNS in women with FI refractory to exercise and medication therapy. Although the improvement in St. Mark’s score after 12 weekly session of PTNS met the threshold of clinical importance, compared to sham stimulation, PTNS did not result in significantly greater improvement in symptom severity, incontinence events, or symptom specific quality of life.

Supplementary Material

Supplementary Table 1
Supplementary Table 2
Supplementary Table 3
Supplementary Figure 1

STUDY HIGHLIGHTS.

WHAT IS KNOWN

  • Fecal incontinence is common and debilitating with few non-invasive treatment options.

  • Percutaneous tibial nerve stimulation (PTNS) is a potential low cost, minimally invasive neuromodulation therapy with conflicting evidence for efficacy.

WHAT IS NEW HERE

  • Though improvement in St. Mark’s score after PTNS exceeded the minimally important difference, PTNS did not differ from sham stimulation in reducing fecal incontinence severity, incontinence events, or quality of life.

ACKNOWLEDGEMENTS

University of Alabama at Birmingham: Danielle Aaron, CRNP, Kathy Carter, RN, David Ellington, MD, Ryanne Johnson, CRNP, Alayne Markland, DO, MSc, Jeannine McCormick, CRNP, Isuzu Meyer, MD, MSPH, R. Edward Varner, MD, Robin Willingham, RN

Brown University Women & Infants Hospital of Rhode Island: Cassandra Carberry, MD, B. Star Hampton, MD, Nicole Korbly, MD, Ann Schantz Meers, BS, RN, Deborah L. Myers, MD, Charles R. Rardin, MD, Kyle Wohlrab, MD, Sarashwathy K. Veera, BS, Elizabeth-Ann R. Viscione, BA

University of California at San Diego: Michael Albo, MD, Marianna Alperin, MD, Stephanie Armstrong, RN, Laura Aughinbaugh, RNP, CNM, Linda Brubaker, MD, Tatiana Catanzarite, MD, Kyle Herrala, Stephanie Micucci, Charles Nager, MD, Dulce Rodriguez-Ponciano, Sandra Romano, LVN, Erika Ruppert; Yahir Santiago-Lastra, MD

Kaiser Permanente San Diego: Keisha Dyer MD, Shawn Menefee MD, Jasmine Tan-Kim MD, Kimberly Ferrante MD, Gouri Diwadkar MD, Christina Doan, Rebekah Dozier, Alyssa David-Tucker, Josephine Salunga, Lynn Hall, Gisselle Zazueta, Linda Mackinnon

Duke University Medical Center: Cindy L. Amundsen, MD, Matthew D. Barber, MD, MHS, Yasmeen Bruton, MA, Nortorious Coleman-Taylor, MA, Cassandra Hanson, WHNP-BC, John E. Jelovsek, MD, MMEd, Amy Kavanagh, MSN, RN-BC, Amie Kawasaki, MD, Shantae McLean, MD, Tracey O’Dowd, RN, John Owens, MSN, RN, Nazema Y. Siddiqui, MD, MHSc, Katelyn C. Smith, FNP-C, Alison C. Weidner, MD, MMCi

University of Pennsylvania: Uduak Andy, Yelizaveta Borodyanskaya, Lorraine Flick, Heidi Harvie, Zandra Kennedy

University of Pittsburgh Magee-Womens Hospital: Mary Ackenbom, Kara Albrecht, Lindsey Baranski, Michael Bonidie, Megan Bradley, Alexus Bushee, Pamela Fairchild, Judy Gruss, Beth Klump, Lauren Kunkle, Jacqueline Noel, Pamela Moalli, Margaret Rajkovic

University of Texas Southwestern: Shanna Atnip, WHNP, Sunil Balgobin, MD, Juanita Bonilla, Agnes Burris, RN, Marlene Corton, MD, Maria Florian-Rodriguez, MD, Christy Hegan, WHNP, Priscilla Reynolds, WHNP, Joseph Schaffer, MD, Alison Schmitt, WHNP, Clifford Wai, MD

RTI International: Andrew Burd, Kate Burdekin, Kendra Glass, Brenda Hair, Michael Ham, Pooja Iyer, James Pickett, Peter Robbins, Amanda Shaffer, Taylor Swankie, Yan Chen Tang, Sonia Thomas, Kevin Wilson, Dennis Wallace

PFDN Data Safety and Monitoring Board members: Paul Tulikangas, University of Connecticut Hartford Hospital, Jenifer D. Ihm, Patient Advocate, Lan Kong, Penn State University College of Medicine, Donna McClish, Virginia Commonwealth University, Katharine O’Dell, UMass Memorial Medical Center, Lea Perez, KLP Consulting LLC, Leslie Rickey, Yale New Haven Hospital, David Shade, The Johns Hopkins University, Ashok Tuteja, University of Utah, Susan Yount, Frontier Nursing University, Lexington KY

FINANCIAL SUPPORT

Eunice Kennedy Shriver National Institute of Child Health and Human Development, and NIH Office of Research on Women’s Health

2 UG1 HD069006, 2 UG1 HD041261, 2 UG1 HD069013, 2 UG1 HD069010, UG1 HD054214, 2 UG1 HD041267, 2 U24 HD069031

CONFLICT OF INTEREST / DISCLOSURE STATEMENT:

Holly E. Richter: Research funding: Renovia, Allergan, NIA/UTSW, NICHD, NIDDK;

Royalties: Up to Date

Travel reimbursement related to editor duties Obstet Gynecol & IUJ

Board: Worldwide Fistula Fund

DSMB: Bluewind

CME speaker: Symposia Medicus

Emily S. Lukacz Consultant: Axonics & Urovant outside of submitted work

Royalties: UpToDate

Research support: Boston Scientific & Cogentix/Uroplasty

David D. Rahn Research support: Pfizer

Anthony G. Visco NinoMed, outside of submitted work

Donna Mazloomdoost Grant: Boston Scientific

Halina Zyczynski Board: American College Obstetrics and Gynecology (no salary compensation)

Benjamin Carper report no conflicts of interest

Marie G. Gantz report no conflicts of interest

Vivian W. Sung report no conflicts of interest

Lily A. Arya report no conflicts of interest

Footnotes

TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT 03278613

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1
NIHMS1763372-supplement-Supplementary_Table_1.docx (25.8KB, docx)
Supplementary Table 2
NIHMS1763372-supplement-Supplementary_Table_2.docx (16.4KB, docx)
Supplementary Table 3
NIHMS1763372-supplement-Supplementary_Table_3.docx (48.1KB, docx)
Supplementary Figure 1
NIHMS1763372-supplement-Supplementary_Figure_1.jpg (86.9KB, jpg)

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