Randomized Trial of Percutaneous Tibial Nerve Stimulation Versus Sham Efficacy in the Treatment of Overactive Bladder Syndrome: Results From the SUmiT Trial

Results 

A total of 220 ambulatory adult subjects were enrolled and randomized with 110 subjects in each arm (fig. 2). Baseline characteristics were homogeneous across intervention arms with females accounting for 86 (78.2%) PTNS subjects and 88 (80.0%) sham subjects. Mean age of subjects was 62.5 and 60.2 years, with 56 (50.9%) and 46 (41.8%) older than 65 years for PTNS and sham subjects, respectively (table 1).

View Large Image Download to PowerPoint

Figure 2. CONSORT diagram (Consolidated Standards of Reporting Trials).

Table 1. Subject baseline characteristics

		PTNS	Sham
	Mean ± SD body mass index	29.1±6.8	30.1±7.8⁎
	No. white subjects (%)	102(92.7)	103(93.6)
	Mean ± SD yrs OAB history	10.2±11.5	9.8±10.4
	No. use of OAB medication within 6 mos (%)	72(66.4)	76(69.1)

No significant differences between treatment arms.

⁎ Of 107 subjects.

An intent to treat analysis of the primary end point demonstrated 54.5% (60 of 110) of PTNS subjects compared to 20.9% (23 of 110) of sham subjects responding to the GRA as being moderately or markedly improved on overall bladder symptoms from baseline (fig. 3). The primary end point analysis showed that PTNS was effective and statistically significant (p <0.001) compared to the sham for improvement in overall bladder symptoms. The primary end point in an as-followed completer analysis of those subjects assessed at 13 weeks demonstrated similar statistically significant results with 58.3% (60 of 103) of PTNS subjects compared to 21.9% (23 of 105) of sham subjects reporting GRA as being moderately or markedly improved on overall bladder symptoms from baseline (table 2). Assessment of treatment effects for the primary efficacy end point by investigational site showed no evidence of a significant association between investigational site and treatment outcome.

View Large Image Download to PowerPoint

Figure 3. Intent to treat analysis comparing PTNS and sham GRA at week 13 assessment.

Table 2. GRA improvement at 13 weeks compared to baseline

		No./Total No. PTNS (%)	No./Total No. Sham (%)	p Value
	Overall bladder symptoms (intent to treat)	60/110(54.5)	23/110(20.9)	<0.001
	Overall bladder symptoms	60/103(58.3)	23/105(21.9)	<0.001
	Urinary urgency	44/103(42.7)	24/105(22.9)	0.003
	Urinary frequency	49/103(47.6)	23/105(21.9)	<0.001
	Urinary urge incontinence	39/103(37.9)	23/104(22.1)	0.02

The secondary end point of the GRA subset symptom components for urinary urgency, frequency and urge incontinence demonstrated that PTNS subject results were statistically significant for improvement on all GRA subsets compared to sham. This finding was determined by subject responses of moderately or markedly improved after 13 weeks.

The 3-day voiding diary daily results showed PTNS to be statistically superior to sham in reducing frequency, urinary urge incontinence episodes, nighttime voids, urgency episodes and voids with moderate to severe urgency (table 3). For voided volume PTNS subjects had a statistically significant increase in voided volume from baseline to 13 weeks, whereas the sham group did not. The difference between groups was not statistically significant for voided volume.

Table 3. Voiding diary parameters at baseline and 13 weeks

		Baseline	13 Wks	Change From Baseline	p Value	Difference (PTNS − sham)	p Value
	Mean ± SD PTNS:
	Frequency⁎	12.3±3.2	9.8±2.8	−2.4±2.5	<0.001	−0.9±2.5	0.01
	Nighttime voids†	2.9±1.6	2.1±1.4	−0.7±1.2	<0.001	−0.4±1.3	0.04
	Voided vol‡	169.5±78.9	183.0±75.6	11.4±45.0	0.01	5.5±42.1	0.35
	Mean±SD sham:
	Frequency	12.4±3.0	11.0±3.1	−1.5±2.4	<0.001
	Nighttime voids	2.9±1.7	2.6±1.6	−0.3±1.4	0.02
	Voided vol	168.7±84.0	172.6±90.6	5.9±39.0	0.13
	Median PTNS:
	Moderate to severe urgency§	8.3	3.7	−3.7	<0.0001		<0.001
	Urge incontinence∥	3.0	0.3	−1.3	<0.0001		0.002
	Median sham:
	Moderate to severe urgency	8.0	5.0	−2.0	<0.0001
	Urge incontinence	1.8	1.0	−0.3	<0.0001

⁎ Measured by average number of intentional voids per day (day and night in 3-day voiding diary). † Measured by average number of waking episodes per day (in 3-day voiding diary). ‡ Average voided volume per void (CC) from the 3-day voiding diary (99 for PTNS, 102 for sham due to incomplete diary completion for this measuring parameter). § Measured by the median number of voids per day (in 3-day voiding diary). ∥ Measured by median number of incontinence episodes accompanied by moderate to severe urgency per day (day and night in 3-day voiding diary).

The condition specific OAB-q symptom severity score and quality of life scores showed statistically significant improvement in the PTNS group compared to the sham group (table 4). The SF-36 general health survey quality of life scores showed statistically significant improvement from baseline compared to 13 weeks in the PTNS group in the physical (p = 0.002) and mental (p = 0.049) domain scales. The sham arm did not show statistically significant improvement from baseline compared to 13 weeks, nor was the difference between groups statistically significant. At 13 weeks the percent of subjects who correctly identified their randomized intervention assignment was equivalent between the study groups (52% in the PTNS group and 58% in the sham group), confirming the validity of the sham model.

Table 4. OAB-q change from baseline at 13 weeks

		Symptom Severity Score⁎	Health Related Quality of Life Score†
	PTNS:
	No.	101	103
	Mean±SD change	−36.7±21.5	34.2±21.3
	Sham:
	No.	102	105
	Mean±SD change	−29.2±20.0	20.6±20.6
	Difference (PTNS − sham)	−7.5±20.7	8.2±21.0
	p Value	0.01	0.006

⁎ Lower score is better score. † Higher score is better score.

In total 6 PTNS subjects reported 9 mild or moderate treatment related adverse events consisting of ankle bruising (1 of 110, 0.9%), discomfort at the needle site (2 of 110, 1.8%), bleeding at the needle site (3 of 110, 2.7%) and tingling in the leg (1 of 110, 0.9%). No local treatment related adverse events were reported in the sham group. In addition, no systemic adverse events were experienced in either group.

Discussion 

The results of this study provide strong scientific evidence that the therapeutic effect of PTNS is due to the stimulation of the posterior tibial nerve and is not due to a placebo effect. The intent to treat primary end point of the study demonstrated that 54.5% of PTNS subjects and 20.9% of sham subjects reported GRA as being moderately or markedly improved in their overall bladder symptoms from baseline. The primary end point calculation used a conservative intent to treat analysis where all subjects lost to followup were analyzed as failures to limit bias to the success rate caused by patient dropouts.

With PTNS there was a statistically significant improvement in all GRA subset components compared to the sham intervention. Additionally, objective voiding diary parameters of frequency, urinary urge incontinence episodes, nighttime voids, urgency episodes and voids with moderate to severe urgency were statistically significant in the PTNS group compared to sham. OAB-q and SF-36 quality of life questionnaires provided further support of the primary and other secondary end points for the efficacy of PTNS.

This is the first neuromodulation study to use a published validated sham component.19 When subjects were asked which intervention they believed they received during the study, there was no statistical difference between the groups. This finding confirms that neither group knew which treatment they received, and affirms the integrity of the sham technique and design, further strengthening the validity of these results.

A strength of this study design is the use of a validated realistic sham intervention which would be difficult to replicate for implantable neuromodulation systems that require surgical placement. An advantage of PTNS is that it does not require surgical implantation of a power supply, leads or electrodes, or the use of prophylactic antibiotics.

The results of this study provide level I evidence that PTNS is safe and effective in improving OAB. A recent multicenter, randomized trial (OrBIT Trial) demonstrated that a series of 12 weekly PTNS treatments was comparable to extended-release tolterodine in treating OAB symptoms.7 A long-term followup of the OrBIT Trial evaluated the durability of PTNS benefits and found that 96% of 12-week responder subjects who continued periodic treatments sustained OAB symptom improvements at 1 year followup.24 No significant PTNS related adverse events were noted in these trials.

A limitation of this study is the relatively short followup period of 12 weeks. However, the 12-week followup corresponds to the recommended treatment protocol for PTNS and additional clinical improvement in the sham arm was not expected to increase after this followup period. This is also the usual therapeutic interval used for OAB drug trials.

PTNS represents an excellent option for patients who are unwilling or unable to tolerate systemic antimuscarinic adverse events (dry mouth, constipation, central nervous system effects), those with conditions refractory to medical and behavioral treatments and those who do not wish to have or are not candidates for an implantable surgical device or reconstructive surgery. Future studies of PTNS in combination with behavioral or pharmacotherapy are needed as PTNS does not preclude these interventions. Given that PTNS has been shown in rigorous clinical studies to be effective, durable and comparable to drug therapy in effectiveness, PTNS should be considered a viable treatment for OAB symptoms.

Conclusions 

This multicenter, double-blind, randomized, sham controlled trial provides level I clinical evidence that PTNS therapy is safe and effective in treating OAB symptoms. The compelling efficacy of PTNS as demonstrated in this trial, along with other recently published reports, should have a significant impact on the future clinical management of OAB.