Idiopathic slow-transit constipation (STC) is a subtype of functional constipation (FC), characterized by a delayed colonic transit of feces and the absence of rectal evacuation disorders.1 It is a common diagnosis in 15% to 42% of patients with FC but is regularly diagnosed next to a rectal evacuation disorder, like outlet obstruction.1–3 It is associated with an impaired physical and mental quality of life, interfered personal daily activities, and work productivity loss.4–6

In patients with idiopathic STC refractory to conservative treatment, such as laxatives and retrograde colonic irrigation, surgical interventions may be considered.7–9 However, surgical options like subtotal colectomy are invasive, might be ineffective in relieving complaints, and are associated with a risk of (long-term) morbidity and even mortality.8,10 Sacral neuromodulation (SNM) is a minimally invasive and safe surgical option delivering electrical stimulation to the sacral nerves, with a low risk of complications in both children and adults.11 Although the exact mechanism of action of SNM for functional constipation is poorly understood, it has been shown that suprasensory stimulation induces a colonic motor response by increasing the frequencies of propagating sequences (PS) and high-amplitude propagating sequences (HAPS).12,13 Both PS and HAPS are essential for normal colonic transit and defecation but are deficient in idiopathic STC patients.14 Hence, the main hypothesized working mechanism of SNM is that it enhances the colonic motor response in patients with idiopathic STC.

Evidence on SNM for FC is conflicting and of suboptimal methodological quality.15 As a result, it is not reimbursed by the Dutch health insurance. Three randomized clinical trials (RCT) reported no difference in treatment response between SNM and sham stimulation,16–18 whereas observational studies showed success rates up to 52%.19,20 These conflicting results might be attributable to heterogeneous patient populations and study designs. Most studies do not differentiate between subtypes of FC, or do not stratify results for STC accordingly.11,16,18,21 Only 1 RCT (n=59) exclusively studied refractory idiopathic STC.17

The No.2-Trial aimed to provide evidence of good methodological quality on the comparative effectiveness of SNM versus personalized conservative treatment (PCT) in a homogeneous, idiopathic STC population, refractory to conservative treatment. From October 2016 until December 2021, SNM was conditionally reimbursed in the Netherlands for patients participating in the No.2-Trial. The results of this study will be used to reappraise the reimbursement decision by the Dutch Ministry of Health, Welfare, and Sports.22 We hypothesized that SNM is an effective treatment modality for patients with idiopathic STC refractory to conservative treatment based on a clinically relevant difference of 30% in treatment success between SNM and PCT.

METHODS Trial Design

The No.2-Trial was a multicenter, pragmatic, open-label, randomized clinical trial. Between February 21, 2017 and March 12, 2020, participants were recruited after referral to 2 Dutch hospitals specialized in SNM for FC: 1 university hospital providing secondary and tertiary care [Maastricht University Medical Center+ (MUMC+), Maastricht], and 1 secondary care hospital [Groene Hart Hospital (GHZ), Gouda]. This study was approved by the Medical Research Ethics Committee (MREC) of the Maastricht University Medical Center+ (MUMC+) and was conducted according to the Declaration of Helsinki. No data safety monitoring board was required by the MREC. For quality assurance purposes, the Clinical Trial Center Maastricht monitored data and safety, and serious adverse events were reported to the MREC and the Dutch Health and Youth Care Inspectorate. All authors had access to the study data and reviewed and approved the final manuscript for publication. This trial is registered at ClinicalTrials.gov (NCT02961582), and the protocol has been published previously.22

Patients

Patients aged 14 to 80 years were deemed eligible when they defecated <3 times per week, fulfilled at least 1 additional item of the Rome-IV criteria for FC,23 were diagnosed with idiopathic STC (objectified by radio-opaque marker study, colonic transit time >62 h24), and were refractory to conservative treatment. The latter was defined as being unresponsive to maximal conservative (nonoperative) treatment, consisting (of a combination) of lifestyle changes, first-line oral and/or rectal laxatives such as lactulose, macrogol, and bisacodyl, second-line laxatives, such as linaclotide and prucalopride, enemas, and retrograde colonic irrigation. To exclude STC patients with co-existing outlet obstruction, all patients underwent a defecography next to the radio-opaque marker study. Defecating proctograms were assessed by a dedicated abdominal radiologist and colorectal surgeon of the study sites, and patients were excluded in case of anatomic disorders such as (internal) prolapse and/or functional outlet obstruction (eg, not being able to relax pelvic floor muscles). In case of functional outlet obstruction, patients were offered pelvic floor physiotherapy, after which the defecography was repeated, and patients’ eligibility for the study was reassessed. Other exclusion criteria included congenital or organic bowel pathology, rectal prolapse, and previous large bowel or rectal surgery. The complete list of inclusion and exclusion criteria is provided in Supplemental Digital Content Fig. 1, Supplemental Digital Content 1, https://links.lww.com/SLA/E949.

Sacral Neuromodulation Treatment

Patients were randomly assigned to SNM or PCT, respectively the experimental and control group of this study, in a 3:2 ratio after completion of baseline questionnaires, using the web-based ALEA software (TenALEA consortium, Amsterdam, the Netherlands) operated by research staff. This randomization ratio was chosen to facilitate the inclusion of participants. Randomization by minimization was performed using the study center, age category (14–17 or 18–80 y), and sex as minimization factors. As SNM, a surgical intervention, was compared with conservative treatment, patients and surgeons could not be blinded. Investigators performed the majority of analyses on a data set using random coding for the treatment arm.

Patients allocated to SNM underwent 2 surgical procedures under local or general anesthesia. During the first procedure, a quadripolar tined lead (InterStim 3889, Medtronic Inc., MN, USA) was inserted into the sacral S3 or S4 foramen and connected to an external neurostimulator (InterStim Verify 3051, Medtronic Inc., MN, USA), followed by a 4-week test stimulation period. After a successful test stimulation, defined as an average defecation frequency ≥3 per week based on a 3-week defecation diary, the external neurostimulator was replaced by an implantable pulse generator (IPG) (InterStim 3058, Medtronic Inc., MN, USA). After a nonsuccessful test stimulation, the tined lead was removed, and the patient returned to a personalized treatment algorithm. Detailed operative procedures are published elsewhere.25

Patients with an implanted IPG were allowed to use additional conservative (nonoperative) treatment such as (combinations of) oral or rectal laxatives, enemas, or retrograde colonic irrigation during the course of the study period, except for during defecation diary assessments.

Personalized Conservative Treatment

The PCT group was the control group of this study. Patients allocated to PCT continued care as usual (ie, conservative nonoperative treatment) under the guidance of their referring physician and equal to their treatment before study participation. In general, this consisted of (a combination of) lifestyle changes, first-line oral and/or rectal laxatives such as lactulose, macrogol, and bisacodyl, second-line oral and laxatives such as linaclotide and prucalopride, enemas, and retrograde colonic irrigation. These patients were not offered any additional types of treatment by the physicians of the study team. Treatment of PCT patients was documented in case report forms.

Outcomes

The primary outcome was treatment success at 6 months follow-up. In the SNM group, due to the period between randomization and the first surgical procedure, the primary outcome was measured 6 months post-lead implantation, whereas, in PCT patients, the primary outcome was measured 6 months post-randomization. Treatment success was defined as an average defecation frequency of ≥3 per week, based on the number of spontaneous bowel movements in the course of a 3-week defecation diary. Spontaneous bowel movements were defined as bowel movements without the use of laxatives, enemas, and/or colonic irrigation. To provide more insight into the effect of SNM on the defecation frequency over time, the difference in the trends of the average defecation frequency per week over time between SNM and PCT was assessed.

Secondary outcomes were the percentage of patients with a 50% reduction in the proportion of defecations with straining and in the proportion of defecations with a sense of incomplete evacuation compared with baseline (3-week defecation diaries); constipation severity (Wexner Constipation Score); fatigue (Dutch fatigue questionnaire); constipation-specific quality of life [Patient Assessment Of Constipation Quality Of Life (PAC-QOL)]; generic health-related (HR) quality of life (QOL) [EuroQol-5D-5L (EQ-5D-5L), ICEpop CAPability measure for Adults (ICECAP-A) in adults (18–80 y), KIDSCREEN-27 in adolescents14–17]; and adverse events (reported in case report forms).

Data Collection

Outcomes were assessed at baseline, 1, 3, and 6 months follow-up. SNM patients with an IPG at 6 months follow-up completed a subsequent outcome measurement at 12 months. An overview of outcome measurements is provided in Supplemental Digital Content Table 1, Supplemental Digital Content 1, https://links.lww.com/SLA/E949. Data were entered into an electronic case report form programmed in the online MACRO electronic data capture system (Clinical Trial Center Maastricht, the Netherlands). Patients were followed from February 21, 2017, until July 31, 2021.

During the diary assessments, patients in both treatment arms were asked to abstain from (additional) conservative (nonoperative) treatments. Patients who did not pass any stool for 3 consecutive days were allowed to use rescue therapy, such as oral and/or rectal laxatives, enemas, and/or colonic irrigation, on every fourth day. This was documented in the diary and was allowed to prevent patients from not passing stools during the 3-week assessment periods. The successful defecation attempts on rescue therapy days were not taken into account when calculating the average defecation frequency per week.

Statistical Analysis

For the primary outcome, success rates of 35% for SNM and 5% for PCT were estimated. This absolute difference in success rates of 30% was considered clinically relevant and was chosen due to the invasive nature of the treatment and the difference being higher than the estimated general placebo effect of 26% in chronic constipation.26 A sample size of 64 patients, with an estimated drop-out rate of 5% (n=3), was required to achieve sufficient statistical power (80%) with a type-I error rate of 5%.

Statistical analyses were performed with SPSS (IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp) according to intention-to-treat (ITT). For the primary outcome, withdrawn patients were classified as treatment failures, and any violation of the rescue therapy protocol during the diary assessment was managed conservatively: successfully treated patients with SNM who violated the protocol were recoded into treatment failures, whereas successfully treated patients with PCT who violated the protocol remained treatment successors.

Statistical significance was defined as P values of 0.05 or less. Multiple imputation with fully conditional specification was used to impute missing data for secondary outcome analyses. The number of imputations was set to 10 and imputed values were drawn using predictive mean matching. Patients without any post-randomization measurements were not taken into account in the analysis of secondary outcomes.

Dichotomous outcomes were expressed as frequencies (%), and continuous outcomes were expressed as means (standard deviation) and medians (interquartile range). Logistic and linear regression, adjusted for randomization minimization factors and the effect of potential unbalanced distributions of baseline variables, were used to analyze differences in secondary outcomes between treatment arms at 6 months for dichotomous and continuous outcomes, respectively. Results from logistic regression analysis were quantified as odds ratio (OR). A multivariable linear mixed-effect model with a random intercept was used for analyzing differences in average defecation frequency per week during the 6 month follow-up period.

Analysis of 12-month outcomes was conducted in the eligible subset of patients with an IPG at 6 months follow-up. Similar to the primary outcome analysis, withdrawn patients were classified as treatment failures. The paired-sample t-test was used to compare continuous scores between 6 and 12 months. This study was reported according to the CONSORT statement (see checklist).

RESULTS

Between January 1, 2017, and March 12, 2020, 67 patients (n=35 MUMC+; n=32 GHZ) were enrolled and randomly assigned in a 3:2 ratio to receive SNM (n=41) or PCT (n=26). At the time the 64th patient was included, 6 out of 64 (9.4%) patients were lost to follow-up or had decided to withdraw from the study. The 3 lost to follow-up/withdrawn patients above the estimated drop-out rate of 5% (3 out of 64) were replaced, resulting in 67 patients. Hereafter, patients were no longer replaced. At the end of the study, in total, 10 (14.9%) patients were lost to follow-up (n=3 SNM, n=4 PCT) or had decided to withdraw (n=2 SNM, n=1 PCT) from the study (Fig. 1, CONSORT flow chart). Two of the lost to follow-ups in the PCT group were excluded from secondary outcome analyses due to missing post-randomization measurements. In the primary outcome analysis, these patients were considered treatment failures according to study criteria (ie, withdrawn patients were classified as treatment failures).

FIGURE 1:

No.2-Trial randomization and follow-up. * Two lost to follow-up patients in the personalized conservative treatment group were excluded from secondary outcome intention-to-treat analyses as no post-randomization measurements were available, and therefore, multiple imputation results were not reliable. DF indicates defecation frequency; IPG, implantable pulse generator; ITT, intention-to-treat; PCT, personalized conservative treatment; SNM, sacral neuromodulation; STC, slow-transit constipation.

Patient Characteristics

Baseline demographic and clinical characteristics were balanced between groups, except for unbalanced baseline EQ-5D-5L utility scores [mean (SD) SNM 0.514 (0.281) vs. PCT 0.346 (0.266)] (Table 1) (Supplemental Digital Content Table 2, Supplemental Digital Content 1, https://links.lww.com/SLA/E949 for characteristics per study site). Small baseline differences in the same direction as the EQ-5D-5L utility scores were also observed in the PAC-QOL and the adult ICECAP-A scores. In all 41 patients allocated to SNM, tined leads were inserted in S3 (n=38) and S4 (n=3) during the first SNM procedure. In 31 (75.6%) out of these 41 patients, according to study criteria (ie, average defecation frequency ≥ 3 per week), an IPG was implanted after a successful test stimulation (Supplemental Digital Content Fig. 2, Supplemental Digital Content 1, https://links.lww.com/SLA/E949 for SNM patient flow).

TABLE 1 - Baseline Demographic and Clinical Characteristics of Patients SNM (n=41) PCT (n=26) Sex  Female 38 (92.7) 24 (92.3)  Male 3 (7.3) 2 (7.7) Age (y) 31 (18–52) 32 (19–44)  Adolescents (14–17 y) 10 (24.4) 5 (19.2)  Adults (18–80 y) 31 (75.6) 21 (80.8) BMI (kg/m2) 23.5 (19.9–25.7) 22.9 (21.3–26.3) Smoking  No 35 (85.4) 20 (76.9)  Yes 6 (14.6) 6 (23.1) Previous surgery  No 19 (46.3) 11 (42.3)  Yes 22 (53.7) 15 (57.7) Duration of constipation (y) 15 (8-22) 14 (8-25) Colonic transit time (h) 120 (94-143) 113 (84–132) Rome-IV criteria (in >25% of defecations…)  Straining 34 (82.9) 21 (80.8)  Lumpy or hard stools 32 (78.0) 22 (84.6)  Sensation of incomplete evacuation 38 (92.7) 23 (88.5)  Sensation of anorectal obstruction/blockage 23 (56.1) 18 (69.2)  Manual manoeuvres to facilitate 4 (9.8) 3 (11.5)

Values are n (%) and median (IQR).

BMI indicates body mass index; IQR, interquartile range; PCT, personalized conservative treatment; SNM, sacral neuromodulation.

Primary Outcome

In the primary ITT analysis, with drop-outs considered as treatment failures, the treatment success rate after 6 months of follow-up differed significantly between the groups: 22 of 41 (53.7%) SNM patients achieved treatment success versus 1 of 26 (3.8%) patients with PCT (OR 36.4, 95% CI 3.4–387.5, P=0.003). There was a significant trend over time in the estimated average defecation frequencies per week between both groups in favor of SNM across all outcome measurements (Fig. 2A, regression coefficient 4.54, 95% CI 2.49–6.59, P<0.001).

FIGURE 2:

(A–C) Changes in average defecation frequency per week and proportion of defecations associated with straining and a feeling of incomplete evacuation. The “n” in the bars represents the eligible number of patients in the treatment arm for the respective analysis. (A) Mean (SD) defecation frequency after multiple imputations, unadjusted for rescue therapy protocol violations. (B and C) Nonimputed percentages were calculated for the subset of patients with a baseline defecation frequency > 0 and nonmissing follow-up measurements with a defecation frequency > 0. PCT indicates personalized conservative treatment; SNM, sacral neuromodulation.

Secondary Outcomes

Clinically meaningful but not significant between-group differences were observed regarding the proportion of defecations associated with a ≥50% reduction in defecations with straining (Fig. 2B, OR 18.2, 95% CI 0.67–497.50, P=0.085) and defecations with a feeling of incomplete evacuation (Fig. 2C, OR 14.9, 95% CI 0.64–346.17, P=0.092) after 6 months of follow-up. Significant between-group differences after 6 months of follow-up, in favor of SNM, were observed in Wexner constipation scores, fatigue scores, PAC-QOL scores, EQ-5D-5L utility and VAS scores, and adult ICECAP-A capability scores (Table 2) (Supplemental Digital Content Table 3, Supplemental Digital Content 1, https://links.lww.com/SLA/E949 and 4, Supplemental Digital Content 1, https://links.lww.com/SLA/E949 for results per study site). There were no significant differences between the groups regarding any of the adolescent (HR)QOL KIDSCREEN-27 domain scores. When compared with baseline, all secondary outcomes in SNM patients were significantly improved, whereas in patients with PCT, the majority of the outcomes were not improved (Table 2). An overview of the follow-up data across all outcome measurements (ie, 1, 3, and 6 months follow-up) is provided in Supplemental Digital Content Table 5, Supplemental Digital Content 1, https://links.lww.com/SLA/E949.

TABLE 2 - Baseline and Six Months Follow-up Secondary Outcome Measures Baseline 6 months follow-up SNM (n=41) PCT (n=26) SNM (n=41) PCT (n=24) Differences in means at 6 mo (SNM vs PCT, 95% CIs)† P Defecation frequency per week 0.71 (0.74) 0.56 (0.78) 5.33 (4.81)* 1.64 (3.87) 4.32 < 0.001 0.33 (0.00–1.33) 0.33 (0.00–0.75) 4.53 (2.32–7.55) 0.33 (0.00–1.00) (2.01 to 6.64) — Wexner Constipation Score‡ 19.10 (4.39) 19.15 (3.56) 11.81 (4.56)* 18.81 (4.36) −7.29 < 0.001 19.00 (17.00–22.00) 19.00 (16.75–21.25) 12.00 (8.00–14.90) 18.40 (15.53–21.00) (−9.72 to −4.87) — Fatigue Score§ 22.33 (4.98) 24.46 (3.28) 16.20 (6.94)* 22.60 (5.23) −6.39 < 0.001 23.0 (18.00–27.00) 25.50 (21.75–28.00) 16.9 (10.35–21.00) 24.50 (18.78–26.75) (−9.61 to −3.16) — PAC-QOL∥ 2.63 (0.52) 2.83 (0.56) 1.40 (0.79)* 2.48 (0.71)* −1.07 < 0.001 2.69 (2.34–2.97) 2.74 (2.51–3.20) 1.49 (0.69–1.93) 2.49 (1.80–3.10) (−1.47 to −0.67) — Physical discomfort 2.95 (0.70) 3.07 (0.62) 1.60 (1.00)* 2.69 (0.88) −1.14 < 0.001 3.00 (2.56–3.50) 3.13 (2.50–3.56) 1.50 (0.75–2.49) 2.70 (2.02–3.44) (−1.64 to −0.64) — Psychosocial discomfort 1.72 (0.79) 2.17 (0.88) 0.82 (0.66)* 1.85 (0.84) −0.96 < 0.001 1.69 (1.13–2.00) 2.13 (1.63–2.63) 0.75 (0.25–1.16) 1.74 (1.24–2.25) (−1.34 to −0.57) — Worries/concerns 2.36 (0.91) 2.54 (0.91) 1.23 (0.82)* 2.21 (0.89) −0.88 < 0.001 2.30 (1.55–3.09) 2.69 (1.82–3.29) 1.23 (0.45–1.88) 2.09 (1.45–2.87) (−1.32 to −0.43) — Satisfaction 3.65 (0.37) 3.53 (0.43) 1.97 (1.23)* 3.14 (0.92) −1.30 < 0.001 3.80 (3.60–3.80) 3.60 (3.20–4.00) 1.98 (0.95–3.00) 3.45 (3.00–3.80) (−1.90 to −0.71) — EQ-5D-5L Utility Score¶ 0.514 (0.281) 0.346 (0.266) 0.710 (0.234)* 0.423 (0.256) 0.243 < 0.001 0.613 (0.216–0.774) 0.325 (0.150–0.526) 0.762 (0.564–0.861) 0.405 (0.211–0.674) (0.113 to 0.372) — EQ-5D-5L VAS# 46.87 (18.29) 41.35 (15.78) 64.31 (18.40)* 43.43 (16.26) 19.56 < 0.001 45.00 (35.00–60.00) 40.00 (30.00–56.25) 65.00 (55.30–80.00) 40.00 (31.25–54.78) (10.53 to 28.59) — ICECAP-A Capability Score** 0.73 (0.20) 0.69 (0.19) 0.87 (0.12)* 0.71 (0.14) 0.143 < 0.001 0.80 (0.61–0.92) 0.69 (0.54–0.87) 0.88 (0.82–0.95) 0.70 (0.61–0.84) (0.064 to 0.221) — KIDSCREEN-27††  Physical well-being 30.36 (11.74) 22.46 (10.84) 32.09 (11.35) 27.98 (5.11) 6.75 0.256 25.07 (22.88–40.45) 20.70 (12.13–33.7) 34.67 (25.96–40.45) 28.13 (23.40–32.22) (−4.90 to 18.39) —  Psychosocial well-being 40.01 (8.86) 40.39 (2.06) 43.42 (6.15) 35.94 (5.59) 8.19 0.063 36.66 (34.88–45.66) 40.39 (38.48–42.31) 41.80 (39.10–49.61) 33.15 (31.94–41.33) (−0.43 to 16.80) —  Parent relations and autonomy 51.46 (5.57) 58.30 (5.94) 49.15 (6.33) 54.99 (6.26) −3.16 0.475 51.21 (47.23–55.75) 59.06 (52.23–63.99) 49.57 (44.94–53.88) 51.21 (50.34–61.53) (−11.84 to 5.52) —  Social support and peers 42.15 (19.82) 50.44 (5.29) 44.14 (13.83) 48.21 (8.49) −4.02 0.626 46.92 (22.50–57.83) 49.79 (45.66–55.53) 45.12 (38.90–54.38) 49.79 (40.11–55.53) (−20.18 to 12.14) —  School environment 40.44 (11.73) 40.64 (9.05) 47.95 (4.23) 47.05 (8.11)* 2.29 0.553 45.38 (32.58–48.08) 40.72 (31.67–49.58) 48.0 (44.61–48.71) 45.38 (40.81–54.13) (−5.30 to 9.88) —

Values are means (SD) and medians (IQR) after multiple imputation.

*Significant (P<0.05) change from baseline.

†Linear regression adjusted for randomization factors and unbalanced baseline covariates.

‡Scores range from 0 (best) to 30 (worst).

§Scores range from 4 (best) to 28 (worst).

∥Scores range from 0 (best) to 4 (worst) for both overall and subscale scores.

¶Scores range from -0.446 (worst) to 1.000 (best) according to the Dutch value set.

#Scores range from 0 (worst) to 100 (best).

**Only measured in adult patients (SNM n=31, PCT n=21 at baseline and n=19 at six months follow-up), scores range from 0.000 (worst) to 1.000 (best) according to the UK value set.

††Only measured in adolescent patients (SNM n=10, PCT n=5), each domain has its specific scoring range (see KIDSCREEN handbook23).

EQ-5D-5L indicates EuroQol-5D-5L; ICECAP-A, ICEpop CAPability measure for Adults; IQR, interquartile range; PAC-QOL, Patient Assessment of Constipation-Quality Of Life; PCT, personalized conservative treatment; SNM, sacral neuromodulation; VAS, Visual Analogue Scale.

In the SNM group, 30 patients [mean age 36 y, 27 (90%) females] were eligible for 12 months follow-up, of which 7 were lost to follow-up or withdrawn (Fig. 1). This patient group was equally distributed over the study centers (n=12 MUMC+, n=13 GHZ), and had a similar age category distribution as the ITT SNM group (23% adolescents, 77% adults). After 12 months of follow-up, 14 out of 30 (46.7%) patients achieved treatment success, and the average defecation frequency per week was 6.3 per week (Fig. 3A). A ≥50% reduction in the proportion of defecations with straining and defecations associated with a feeling of incomplete evacuation was reported in, respectively, 73.3 and 62.5% of the patients. No significant differences were observed between 6 and 12-month outcome measurements for the average defecation frequency per week (P=0.750), Wexner constipation scores (P=0.328), EQ-5D-5L utility scores (P=0.839), and EQ-5D-5L VAS scores (P=0.218) (Fig. 3A,B,C). When compared with baseline, these secondary outcomes were significantly improved for both 6 and 12-month follow-up.

FIGURE 3:

(A–C) Six and 12-month outcome measures for the subset of patients with an implantable pulse generator at 6 months follow-up (n=30). Values are means (SD) after multiple imputations. (A) Mean (SD) defecation frequency per week and Wexner Constipation scores. Wexner Constipation scores range from 0 (best) to 28 (worst). (B) Mean (SD) EQ-5D-5L utility scores ranging from −0.446 (worst) to 1.000 (best) according to the Dutch value set. (C) Mean (SD) EQ-5D-5L VAS scores ranging from 0 (worst) to 100 (best). DF, defecation frequency; EQ-5D-5L, EuroQol-5D-5L; VAS, visual analogue scale.

Adverse Events

Eight serious adverse events were reported in 7 patients: 6 emergency hospital admissions (n=4 SNM, n=2 PCT) attributed to underlying constipation complaints, 1 hospital admission after a perforated appendix, and COVID-19 infection in the SNM group, not attributed to constipation or SNM, and 1 laryngospasm resulting in desaturation, attributed to the anesthesia during the SNM procedure. Furthermore, 78 adverse events (n=68 SNM, n=10 PCT) were reported in 41 (n=32 SNM, n=8 PCT) patients. The total list of (serious) adverse (device) events is presented in Supplemental Digital Content Table 6, Supplemental Digital Content 1, https://links.lww.com/SLA/E949.

Thirty-two adverse events were typical for SNM. The most reported events included persistent pain/discomfort at the IPG implantation site (n=10), after which 6 IPGs were repositioned; tingling/painful feeling in leg/labia (n=7); and postoperative pain at the wound site (n=3). Three adverse device events were reported: 1 patient underwent 2 lead revisions due to lead defects and 1 patient experienced a software defect of the IPG-programmer. No patients were explanted as a result of adverse events or complete loss of effectiveness. In the PCT group, the most frequently reported adverse events were elective hospital admission for clinical laxation (n=3), colostomy (n=2), and vasovagal complaints (n=2).

DISCUSSION

This multicenter, open-label, pragmatic RCT in patients with refractory idiopathic STC demonstrated a clinically relevant and significant difference in treatment success after 6 months of follow-up between SNM (53.7%) and PCT (3.8%). When compared with PCT, clinically relevant and statistically significant improvements were observed in constipation severity, fatigue, and disease-specific and generic (HR)QOL scores of the SNM group. Adolescent (HR)QOL scores did not differ significantly between both groups after 6 months of follow-up, which might be attributable to the small number of adolescents included in the study.

Despite the positive effect of SNM, the STC burden was not completely reduced. After 6 months, patients in both groups were considered to be “extremely fatigued” compared with the Dutch pop