InSite: Sacral Neuromodulation Versus Standard Medical Therapy for Overactive Bladder
InSite was a multicenter, open-label randomized trial of sacral neuromodulation (InterStim) versus standard medical therapy with antimuscarinic drugs in 147 adults with overactive bladder who had failed at least one anticholinergic, with OAB therapeutic success at 6 months as the primary endpoint. In the intention-to-treat analysis, success was 61% with neuromodulation and 42% with medical therapy (P = 0.02).[1]
- Design and population
- Multicenter, open-label randomized superiority trial with nonrandomized implanted cohort. Adults with bothersome overactive bladder (urge incontinence of at least 2 leaks per 72 hours and/or at least 8 voids per day) who had failed at least one anticholinergic and had at least one not yet tried; 93% were women and mean age was 58.
- Arms
- Sacral neuromodulation (InterStim) versus standard medical therapy with antimuscarinic drugs
- Report and follow-up
- 2014 · 6 months
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| 6-month OAB therapeutic success, intention to treat; risk difference in percentage points (SNM minus medical therapy) | 61% vs 42% | difference 19; P 0.02 | Met |
Harms: Adverse events related to the assigned treatment: 18/59 (30.5%; device-related, lead implanted) vs 21/77 (27.3%; medication-related)
Design
The protocol had two phases: a randomized comparison of at least 60 subjects per arm, and a nonrandomized phase in which all qualified subjects received InterStim. It doubled as the FDA-mandated post-approval study of the tined lead placed by a minimally invasive approach, so the registered co-primary endpoint for the implanted cohort was the 5-year rate of lead-related adverse events requiring surgery, with an upper confidence bound required to stay below 0.33. Thirty-eight centers enrolled 571 subjects from November 2007 to March 2011, 243 of them in the randomized cohort, where 96 were excluded for eligibility failure before randomization.[2]
Eligible adults had urge incontinence (at least 2 leaks per 72 hours) and/or urgency-frequency (at least 8 voids per day), had failed at least one anticholinergic and had at least one not yet tried. They stopped OAB medication before and during the baseline diary and were then randomized 1:1.[1] Exclusions included neurologic disease such as multiple sclerosis or complete spinal cord injury, urinary tract obstruction, stress-predominant or mixed incontinence in which the stress component overrides the urge component, botulinum toxin treatment in the previous 12 months, and symptomatic urinary tract infection.[2]
Therapeutic success was at least 50% improvement in average leaks per day for subjects with urge incontinence, and at least 50% improvement in voids per day or a return to fewer than 8 voids per day for subjects with urgency-frequency. The comparator was a choice among oral and transdermal antimuscarinics (oxybutynin, solifenacin, tolterodine, trospium, darifenacin, fesoterodine). The registered primary hypothesis for the randomized cohort was a greater response rate with InterStim.[2]
Results
Of 147 randomized subjects (70 to neuromodulation, 77 to medical therapy; 93% women, mean age 58), 6-month intention-to-treat success was 61% with neuromodulation and 42% with medical therapy, a difference of 19 percentage points (P = 0.02). In the as-treated analysis, success was 76% versus 49% (P = 0.002). Among subjects with baseline and 6-month quality-of-life assessments, 86% in the neuromodulation group reported improved or greatly improved urinary symptom interference, compared with 44% in the medical therapy group, and quality-of-life improvements were greater with neuromodulation (all P < 0.001).[1]
Of 272 implanted subjects, 5-year therapeutic success was 67% (95% CI 60–74%) among 183 in a modified completers analysis and 82% (95% CI 76–88%) among 150 completers. At baseline, 202 subjects with urge incontinence averaged 3.1 ± 2.7 leaks per day and 189 with urgency-frequency averaged 12.6 ± 4.5 voids per day; among 5-year completers, mean reductions were 2.0 ± 2.2 leaks and 5.4 ± 4.3 voids per day, respectively (both P < 0.0001). These 5-year figures come from a single-arm cohort that includes the nonrandomized subjects.[3]
Surgery and treatment delivery
Of 340 subjects who completed test stimulation, 272 (80%) received a permanent implant; 91% were women and mean age was 57.[3][4] In the registry record, subjects in each group went through test stimulation and received a full system implant if it was successful. After the month 6 visit, subjects in the medical therapy group could choose test stimulation and, if successful, an implant. In the randomized cohort, 59 of 70 subjects in the neuromodulation group and 71 of 77 in the medical therapy group completed the 6-month visit.[2]
With the tined lead, the registry's 5-year cumulative probability of lead-related adverse events requiring surgery was 22.4% (95% CI 16.6–27.7%), below the prespecified limit of 0.33. Cumulative 5-year probability of lead migration was 5.9% (95% CI 2.9–8.9%) and of lead-associated infection 1.2% (95% CI 0–2.5%).[2]
Adverse events
In the randomized phase, device-related adverse events occurred in 18 of 59 neuromodulation subjects with a lead implant (30.5%), and medication-related adverse events occurred in 21 of 77 medical-therapy subjects (27.3%).[1]
In the 272 implanted subjects, adjudicated device-related adverse events through 12 months occurred in 82 (30%), only one serious, and 56% of them arose between implant and 3 months. The most frequent were undesirable change in stimulation (32 subjects, 12%), implant site pain (20, 7%) and implant site infection (9, 3%). The surgical intervention rate was 13%, from pain at the surgical site (4%), lack or loss of efficacy (4%) and infection (3%), most often revision or replacement. Of 26 pain events, 13 required surgery and 2 led to explant. Ten subjects had 13 surgical site infection events; 5 resolved with antibiotics and 8 required explantation.[4]
By 5 years, the most common device-related adverse events were undesirable change in stimulation (60 of 272, 22%), implant site pain (40, 15%) and therapeutic product ineffectiveness (36, 13%).[3]
Limitations
Treatment was unmasked, and the randomized comparison ended at 6 months, after which medical therapy subjects could cross to test stimulation. Medtronic sponsored the study.[2] The comparator was any of several antimuscarinics rather than a fixed regimen, and the primary success definition combined leak and void-frequency criteria across two symptom phenotypes. The 5-year results describe implanted subjects only, so they exclude those who failed test stimulation and carry no comparator.[1][3]
In conversation
- Built on by ARTISAN-SNM (2019). The authors compared responder-rate analysis, neurostimulator-site pain and lead migration with InSite's non-rechargeable InterStim experience.
Same setting ROSETTA (2016)
InSite compared neuromodulation with antimuscarinics, while ROSETTA compared it with 200 U onabotulinumtoxinA in women with refractory urgency incontinence and reported the change in daily urgency incontinence episodes rather than a success rate.[5][7]
Guidelines and approvals
- AUA/SUFU (2024). Clinicians should offer sacral neuromodulation, percutaneous tibial nerve stimulation and/or intradetrusor botulinum toxin injection to patients with OAB who have an inadequate response to, or intolerable side effects from, pharmacotherapy or behavioral therapy . The guideline text reviews InSite as the randomized comparison of neuromodulation with antimuscarinics.[5]
- EAU (limited update, March 2026). Offer sacral nerve stimulation to women with OAB or urgency urinary incontinence refractory to anticholinergic therapy . The summary of evidence rates sacral nerve stimulation as more effective than continuation of failed conservative management, with no sham controls used, at level of evidence 1b.[6]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2014-01-10 | 6-month randomized report · primary | — | 6-month OAB therapeutic success, intention to treat; risk difference in percentage points (SNM minus medical therapy): 61% vs 42%; difference 19; P 0.02 Met 6-month OAB therapeutic success, as-treated analysis; risk difference in percentage points (SNM minus medical therapy): 76% vs 49%; difference 27; P 0.002 Improved or greatly improved urinary symptom interference score at 6 months: 86% vs 44%; — | Siegel S, Noblett K, Mangel J, et al. Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder. *Neurourol Urodyn.* 2015;34(3):224-230. DOI |
| 2016-08-04 | Adverse events and interventions to 12 months · secondary | — | — | Noblett K, Benson K, Kreder K. Detailed analysis of adverse events and surgical interventions in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. *Neurourol Urodyn.* 2017;36(4):1136-1139. DOI |
| 2017-07-11 | 5-year follow-up of implanted subjects · updated | — | 5-year therapeutic success among 183 of 272 implanted subjects, modified completers analysis (95% CI 60–74%): 67%; — Descriptive 5-year therapeutic success among 150 of 272 implanted subjects, completers analysis (95% CI 76–88%): 82%; — Descriptive Five-year completers mean reduction; baseline mean 3.1 leaks per day in 202 subjects with urge incontinence at baseline: 2.0 ± 2.2 leaks per day; P <0.0001 Descriptive Five-year completers mean reduction; baseline mean 12.6 voids per day in 189 subjects with urgency-frequency at baseline: 5.4 ± 4.3 voids per day; P <0.0001 Descriptive Cumulative 5-year probability of tined lead related adverse events requiring surgery or revision, all implanted subjects; prespecified upper 95% confidence bound below 0.33: 22.4% (95% CI 16.6–27.7%); — Met | Siegel S, Noblett K, Mangel J, et al. Five-year followup results of a prospective, multicenter study of patients with overactive bladder treated with sacral neuromodulation. *J Urol.* 2018;199(1):229-236. DOI |
References
1. Siegel S, Noblett K, Mangel J, et al. "Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder." Neurourol Urodyn. 2015;34(3):224-230. doi:10.1002/nau.22544
2. ClinicalTrials.gov. "InSite for Over Active Bladder." Identifier NCT00547378. Sponsor: Medtronic. Results first posted December 12, 2017.
3. Siegel S, Noblett K, Mangel J, et al. "Five-year followup results of a prospective, multicenter study of patients with overactive bladder treated with sacral neuromodulation." J Urol. 2018;199(1):229-236. doi:10.1016/j.juro.2017.07.010
4. Noblett K, Benson K, Kreder K. "Detailed analysis of adverse events and surgical interventions in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients." Neurourol Urodyn. 2017;36(4):1136-1139. doi:10.1002/nau.23076
5. Cameron AP, Chung DE, Dielubanza EJ, et al. The AUA/SUFU Guideline on the Diagnosis and Treatment of Idiopathic Overactive Bladder. American Urological Association/Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction; 2024. Statement 25 and Sacral neuromodulation section.
6. Harding CK, Lapitan MC, Arlandis S, et al. EAU Guidelines on Management of Non-Neurogenic Female Lower Urinary Tract Symptoms (LUTS), limited update March 2026. Arnhem: EAU Guidelines Office. Section 4.1.4.c.2.
7. Amundsen CL, et al. "OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial." JAMA. 2016;316(13):1366-1374. doi:10.1001/jama.2016.14617