Medtronic TM90P01 Clinical Study / Summary

Clinical summary

Medtronic InterStim® Therapy

Clinical summary

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Medtronic®, InterStim®, and Itrel® are trademarks of Medtronic, Inc., registered in the
U.S. and other countries.

Table of contents

Urinary control clinical trial results 5

Tined lead (InSite), post-approval study 5

Study objective 5
Study design 6
Final study results, randomized cohort 14
Final study results, all-implanted cohort 20
12-month follow-up results 22
5-year follow-up results 28

Single Stage implant, clinical trial 36

Patients studied 36
Study design and methods 37
Study results 37
Efficacy 38

Staged implant, retrospective study 41

Study results 41
Efficacy 42

Buttock neurostimulator placement, retrospective study 42

InterStim System, post-approval study 43

Patients studied 43
Study design and methods 43

Refer to the appropriate information for prescribers booklet for
contraindications, warnings, precautions, adverse events summary,
individualization of treatment, patient selection, use in specific populations,
resterilization, and component disposal.

Refer to the device implant manual for device description, package contents,
device specifications, battery information, and instructions for use.

Refer to the indications sheet for indications and related information.

Refer to the System Overview and Compatibility Insert for information
regarding device compatibility.

Refer to the System Eligibility, Battery Longevity, Specifications Reference
Manual for neurostimulator selection, battery longevity calculations, and
specific neurostimulator specifications.

Clinical summary 2018-04-01  English 3

Study results 43

Bowel control clinical trial study 48

Study design and methods 48
Study results 52

4 English  Clinical summary 2018-04-01

Urinary control clinical trial results

The safety and efficacy of Medtronic InterStim Therapy has been investigated by five
Medtronic-sponsored studies — one prospective clinical trial, two retrospective studies,
and two post-approval studies:

Tined lead (InSite), post-approval study

▪

Single Stage implant, clinical study

▪

Staged implant, retrospective study

▪

Buttock Neurostimulator Placement, retrospective study

▪

InterStim System, post-approval study

▪

The summaries below present results from the individual studies, as well as
information about the study designs and methods.

The configuration of the neurostimulation systems used in the urinary control studies
included the Model 7424 Itrel II, Model 3023 InterStim
neurostimulator(s), a non-tined lead (Models 3886 or 3080) with a lead extension, or a
tined lead (Models 3889 or 3093).

1

, and/or Model 3058 InterStim II

Tined lead (InSite), post-approval study

Study objective

The InSite trial was designed to be implemented in two phases. Phase one was a
prospective, multi-center, randomized clinical trial comparing Sacral Neuromodulation
(SNM) to conventional medical management (CMM) with a 6-month follow-up period.
Phase two of the InSite trial was a prospective evaluation of the safety and efficacy of
SNM to five years. The objective of phase two was to evaluate the cumulative rate of
adverse events related to the tined lead that required surgery at five years, in addition
to therapy success and improvements in quality of life.

The purposes of this study were:

To provide evidence from a randomized controlled trial that SNM provides better

▪

relief of symptoms of OAB than CMM in current use.
To fulfill the requirements of the FDA-mandated post-approval study of the safety

▪

of the tined lead using a minimally invasive approach.

The primary objectives of the study were:

To demonstrate that the OAB therapeutic success rate at 6 months is greater for

▪

the SNM group than for the CMM group. OAB therapeutic success is defined as:
– at least 50% improvement in average voids/day from baseline or a return to

normal voiding frequency (<8 voids/day) for patients with urinary frequency at
baseline

– at least 50% improvement in average leaks/day from baseline for patients with

urinary incontinence at baseline

1

The Model 3023 InterStim Neurostimulator used in the study is functionally equivalent to the Itrel II
neurostimulator.

Clinical summary 2018-04-01  English 5

Patients with both frequency and incontinence at baseline must meet at least one
of the above criteria to be considered a success.

To demonstrate that the upper bound of the 95% CI for the cumulative 5-year rate

▪

of adverse events related to the tined lead that require surgery after a full system
implant is less than 33%.

The secondary objectives of the study were:

To estimate the suspected cumulative tined lead migration rate at 5 years in

▪

patients with a full system implant.
To characterize the cumulative infection rate, at 5 years, associated with the tined

▪

lead in patients with a full system implant.

Study design

The inclusion criteria were the following:

Have a diagnosis of overactive bladder (OAB) as demonstrated on a 72-hour

▪

voiding diary:
– Urinary urge incontinence, as demonstrated by a minimum of 2 involuntary

leaking episodes in 72 hours

– Urgency-frequency, as demonstrated by greater than or equal to 8 voids per

day

Be male or female and 18 years of age or older

▪

Be able to consent to participate by signing the informed consent

▪

Be willing and able to attend visits and comply with the study protocol including

▪

adequate operation of equipment
Have failed or were not a candidate for more conservative treatment (eg, pelvic

▪

floor training, biofeedback, behavioral modification)
Have failed or could not tolerate (stopped taking medication due to lack of efficacy

▪

or intolerable side effects) at least 1 anticholinergic or antimuscarinic medication
and have at least 1 anticholinergic or antimuscarinic medication not yet attempted

Have been on current regimen of OAB medications or have not been on any OAB

▪

medications for at least 4 weeks prior to beginning the baseline voiding diary

The exclusion criteria were the following:

Have severe or uncontrolled diabetes (defined as being a diabetic with a

▪

hemoglobin A1c of ≥8%; however, subjects with a hemoglobin A1c of ≥8% and
supporting documentation of diabetes control were considered for enrollment) or
diabetes with peripheral nerve involvement

Have concomitant medical conditions that could limit the success of the study

▪

procedure such as: pelvic pain with uncertain etiology, active degenerative disc
disease, bleeding complications, spinal cord injury, or a cerebral-vascular accident
(CVA) within the last 6 months

Have skin, orthopedic, or neurologic anatomical limitations that could prevent

▪

successful placement of an electrode

6 English  Clinical summary 2018-04-01

Have neurological diseases such as multiple sclerosis, clinically significant

▪

peripheral neuropathy, or complete spinal cord injury (eg, paraplegia)
Have knowledge of planned magnetic resonance imaging, diathermy, microwave

▪

exposure, high output ultrasonic exposure, or radiofrequency energy exposure
Have urinary tract mechanical obstruction such as benign prostatic hypertrophy,

▪

cancer, or urethral stricture
Have symptomatic urinary tract infection (UTI); however, upon completion of

▪

therapy for UTI, or if the subject was receiving prophylaxis for UTI, the subject
could be considered for study entry if the subject was symptom-free for 1 month
prior to beginning the baseline voiding diary

Have implanted neurostimulators, pacemakers, or defibrillators

▪

Have primary stress incontinence or mixed incontinence where the stress

▪

component overrode the urge component
Have had treatment of urinary symptoms with botulinum toxin therapy in the past

▪

12 months
Be a woman who was pregnant or planning to become pregnant or was a woman

▪

of child-bearing potential who was not using a medically-acceptable method of
birth control (women of child-bearing potential were to undergo a pregnancy test,
with a clear negative result, no more than 7 days prior to the randomization visit)

Have a life expectancy of less than 1 year

▪

Have plans to enroll in another investigational device or drug trial during their

▪

participation in this study, or were currently enrolled in an investigational device or
drug trial

Design

The clinical study included 2 cohorts: a randomized cohort and an all-implanted cohort.
The randomized cohort included subjects who were randomized 1:1 to either SNM or

CMM and were followed for 6 months. Voiding diary data and questionnaires regarding
symptoms of OAB, depression, sexual function, and pelvic pain were compared
between the 2 treatment groups. After the 6-month visit, patients in the CMM group
could discontinue or go through test stimulation and if successful, receive a full
InterStim system implant. These patients then became part of the all-implanted cohort.

The all-implanted cohort included implanted subjects from the initial randomized cohort
plus additional subjects enrolled in the study after the randomized cohort enrollment
was complete. These additional subjects were not randomized. These non-randomized
subjects went through test stimulation and, if successful, were implanted with the
InterStim Therapy system. All implanted subjects were followed for 5 years, and
completed voiding diaries and questionnaires regarding symptoms of OAB,
depression, sexual function, and pelvic pain. Safety and efficacy data for all-implanted
subjects are reported in this clinical summary for the 12-month and the 5-year follow­ups.

Clinical summary 2018-04-01  English 7

Study population

Subjects with bothersome symptoms of overactive bladder (OAB) including urinary
urge incontinence (UI) and/or urgency-frequency (UF), who failed at least 1
anticholinergic medication and had at least 1 not tried were included.

Sample size

Randomized cohort:
To detect a difference in 6-month OAB therapeutic response rates of 53% for SNM vs.

23% for CMM (two-sided α=0.05 and 80% power), 47 patients per group with 6-month
data were required. To ensure a minimum of 47 subjects per group with 6-month data,
a minimum of 120 subjects (60 SNM, 60 CMM) were randomized.

All implanted cohort:
Assuming the true 5-year rate of adverse events requiring surgery that are related to

the tined lead is 21%, a sample size of 109 implanted patients at 5 years provides at
least 80% power (two-sided α=0.05) to demonstrate that the rate is less than 33%.
Assuming a 10% annual attrition rate, to achieve 109 implanted subjects at 5 years, a
total of 185 subjects were required to receive an implant.

Data source

Electronic diaries were used to collect information about voiding behaviors and leaking
episodes. Voiding diary data provided the primary endpoints for the efficacy analysis.
Patients were scheduled to complete daily voiding diaries for 72 consecutive hours
both at baseline and before each scheduled follow-up visit. All diary data were
summarized as a daily (24-hour) rate. Qualification for the study based on leaks/day
was ≥0.67 leaks/day or ≥8 voids/day.

For efficacy, OAB therapeutic success was defined as:

at least 50% or greater improvement in average leaks/day from baseline for

▪

patients with urinary incontinence at baseline, or
at least 50% improvement in average voids/day from baseline or a return to

▪

normal voiding frequency (<8 voids/day) for patients with urgency-frequency at
baseline.

Patients with both urgency-frequency and urinary incontinence at baseline had to meet
at least 1 of the above criteria to be considered a success.

Quality of life (QOL) data were collected through questionnaires at baseline and
scheduled follow-up visits, using the following validated tools:

The International Consultation on Incontinence Modular Questionnaire (ICIQ)-

▪

OABqol questionnaire provides a measure to assess the impact of overactive
bladder symptoms on quality of life

2

, and consists of 4 subscales (concern,

coping, sleep, and social) and a single item on urinary symptom interference; the

2

Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, et al., Psychometric validation of an
overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life
Res. 2002 Sep;11(6):563-74.

8 English  Clinical summary 2018-04-01

Health-Related Quality of Life (HRQL) overall total score is then calculated from 4
subscales

▪

The Male/Female Lower Urinary Tract Symptoms-Sex (MLUTSsex3 and
FLUTSsex
sexual matters associated with male and female lower urinary tract symptoms in
research and clinical practice

▪

The Beck Depression Inventory II (BDI-II5) is a validated assessment of patients’

4

) are validated patient-completed questionnaires used to evaluate

feelings over 2 weeks
The validated Visual Analog Scale (VAS) was used to assess pelvic pain

▪

associated with urgency

Safety was evaluated through collection and review of adverse events, which were
reported by the investigators and reviewed and adjudicated by an independent Clinical
Events Committee.

Data source, randomized cohort

All randomized subjects were required to discontinue OAB medications for four days
prior to their initial voiding diary.

In the randomized cohort, patients randomized to the SNM group underwent a staged
implant procedure. The staged implant included a test stimulation period where tined
lead(s) were placed. During the last 72 hours of the 14-day at-home test stimulation
period, the patient completed a voiding diary to determine if they qualified for a full
InterStim Therapy system implant. If successful test stimulation was demonstrated
(≥50% improvement from baseline in average leaks/day or voids/day or a return to
normal voiding (<8 voids/day) based on voiding diary parameters), the neurostimulator
was implanted. OAB medication use was restricted for the first 6 months after receiving
a full system implant.

Patients randomized to the CMM group restarted their medication that was
discontinued prior to completion of the baseline diary, or started the next
recommended anticholinergic or antimuscarinic medication. All patients were to return
for the 3-month and 6-month follow-up visits.

Data source, all-implanted cohort

In the all-implanted cohort, additional patients were enrolled in the InSite Study but
were not randomized. These non-randomized patients underwent test stimulation and
if successful, received an InterStim Therapy implant. These additional implanted
patients plus the patients from the initial randomized cohort who were implanted were

3

Frankel SJ, Donovan JL, Peters TI, Abrams P, Dabhoiwala NF, Osawa D, et al., Sexual
dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol. 1998 Aug;51(8):677-85.

4

Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P., The Bristol Female
Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol.
1996 Jun;77(6):805-12.

5

Beck AT, Brown G, Steer RA., Beck Depression Inventory II manual. San Antonio, TX: The
Psychological Corporation, 1996.

Clinical summary 2018-04-01  English 9

followed through 5 years. 12-month results are presented through database freeze on
May 13, 2014. 5-year results are presented through study closure on August 9, 2016.

Key study endpoints, randomized cohort
Efficacy – To demonstrate that the OAB therapeutic success rate at 6 months was

greater for the SNM group than for the CMM group, with OAB success defined as
either a ≥50% improvement in average leaks/day for UI patients or voids/day from
baseline, or a return to normal voiding frequency (<8 voids/day) for UF patients. An
intent-to-treat analysis was conducted, in which all patients were analyzed in the group
to which they were assigned, regardless of treatment received. Patients who failed to
complete follow-up were assumed to be treatment failures. A sensitivity analysis based
on the treatment that patients received (hereafter, “as treated”) was also conducted on
the primary analysis, and only included those patients with both baseline and follow-up
measurements.

Safety – To compare the number of patients experiencing adverse events in the SNM
group with full system implant to the CMM group with no implant.

Additional study measures –To characterize and compare changes in quality of life
from baseline to 6 months in the SNM and CMM groups. Results were reported from
the analyses based on the treatment that subjects received.

Key study endpoints, all-implanted cohort
Safety:

To evaluate the 5-year rate of adverse events related to the tined lead that require

▪

surgery after a full system implant.
To estimate the suspected cumulative tined lead migration rate at 5 years in

▪

subjects with a full system implant.
To characterize the cumulative infection rate associated with the tined lead at 5

▪

years.

Additional study measures at 12 months and 5 years:

To characterize quality of life in patients with OAB treated with SNM. A QOL

▪

completers analysis was presented which included implanted patients who
completed at least one quality of life measure at both baseline and 12 months and
both baseline and 5 years.

To characterize adverse events reported with the use of SNM during both test

▪

stimulation and full system implant through 12 months and 5 years.
To characterize efficacy of SNM in patients with OAB. An analysis including

▪

implanted patients with both baseline and follow-up evaluations, or those who
withdrew early due to a device-related death, device-related adverse event, or
lack of efficacy resulting in explant was conducted (modified completers analysis).
These early withdrawal patients had their missing data imputed to their baseline
assessment and were therefore considered failures (no improvement). Completers
analysis was also reported which included implanted patients with both baseline
and 12-month evaluations and both baseline and 5-year evaluations.

10 English  Clinical summary 2018-04-01

Number of study sites and patients
Baseline demographics

In the randomized cohort, 147 patients were randomized with 70 patients to SNM and
77 patients to CMM. Baseline demographics for the randomized cohort are shown in
Table 1. There were no significant differences between SNM and CMM in baseline
characteristics.

Table 1. Baseline characteristics for randomized patients

Demographics

SNM

(n=70)

a

CMM
(n=77)

a

Gender

Female 66 (94%) 71 (92%)

Male 4 (6%) 6 (8%)

Race

White 61 (87%) 70 (91%)

Black 7 (10%) 7 (9%)

Asian/White 1 (1%) 0 (0%)

Other 1 (1%) 0 (0%)

Ethnicity

Not Hispanic or Latino 67 (96%) 77 (100%)

Hispanic or Latino 3 (4%) 0 (0%)

OAB qualification per study diary

Urinary incontinence only 25 (36%) 27 (35%)

Urgency-frequency only 19 (27%) 16 (21%)

Both 26 (37%) 34 (44%)

Number of previous medications

1 20 (29%) 17 (22%)

2 21 (30%) 28 (36%)

3 14 (20%) 14 (18%)

4-7 15 (21%) 18 (23%)

Age at consent (years) 60.4 ± 14.4 57.1 ± 15.3

Years since diagnosis 9.2 ± 10.5 7.4 ± 7.1

Clinical summary 2018-04-01  English 11

Table 1. Baseline characteristics for randomized patients (continued)

Demographics

Baseline leaks/day

a

SNM

(n=70)

b

2.4 ± 1.7 (n=51) 2.7 ± 1.9 (n=61)

CMM
(n=77)

a

Pads replaced/day 1.1 ± 1.1 (n=51) 1.5 ± 1.5 (n=61)

Urgency of leaks

c

3.0 ± 0.8 (n=51) 3.1 ± 0.8 (n=61)

Baseline voids/day 11.2 ± 2.9 (n=45) 11.9 ± 4.3 (n=50)

Void volume/void (mL)

Urgency of voids

a

± values is the mean plus or minus the standard deviation.

b

Leaks and voids include only those patients who qualified for UI (leaks) or UF (voids) at baseline. A
patient could qualify for both.

c

Urgency of each leak and void was rated on the following scale: 1=no urgency, 2=mild,
3=moderate, 4=severe.

d

Void volume was only summarized for patients reporting volume on at least 50% of their voids.

In the all-implanted cohort, 340 patients underwent test stimulation, and 272 patients
received a full system implant. Baseline demographics for the patients with full system
implant are shown in Table 2.

d

c

157.2 ± 77.0 (n=37) 159.2 ± 87.9 (n=36)

2.9 ± 0.4 (n=45) 3.0 ± 0.5 (n=50)

Table 2. Baseline characteristics for all-implanted patients

Demographics

Total

a

(n=272)

Gender

Female 248 (91%)

Male 24 (9%)

Race

White 243 (89%)

Black 19 (7%)

Asian/White 1 (<1%)

American Indian or Alaska Native/White 2 (<1%)

American Indian or Alaska Native 1 (<1%)

Native Hawaiian or Other Pacific Islander 1 (<1%)

Other 5 (2%)

12 English  Clinical summary 2018-04-01

Table 2. Baseline characteristics for all-implanted patients (continued)

Demographics

Total

a

(n=272)

Ethnicity

Not Hispanic or Latino 262 (96%)

Hispanic or Latino 10 (4%)

OAB qualification per study diary

b

Urinary incontinence only 74 (27%)

Urgency-frequency only 61 (22%)

Both 128 (47%)

Number of medications tried prior to implant

c

160 (22%)

284 (31%)

356 (21%)

4-7 67 (25%)

Age at implant (years) 57.0 ± 14.2

Years since diagnosis 8.3 ± 9.9

Baseline leaks/day

d

3.1 ± 2.7 (n=202)

Pads replaced/day 1.7 ± 2.2 (n=202)

Urgency of leaks 3.0 ± 0.8 (n=202)

Baseline voids/day

Void volume/void (mL)

Urgency of voids

a

± values is the mean plus or minus the standard deviation.

b

Baseline qualification not available for 9 patients either due to invalid diary data or due to CMM
patients not showing OAB symptoms (≥8 voids/day and/or 2 leaks/72 hours) prior to implant.

c

Five patients did not have previous medication prior to implant. They were either protocol
deviations or contraindicated for OAB medication.

d

Leaks and voids include only those patients who qualified for UI (leaks) or UF (voids) at baseline. A
patient could qualify for both.

e

Void volume was only summarized for patients reporting volume on at least 50% of their voids.

f

Urgency of each leak and void was rated on the following scale: 1=no urgency, 2=mild,
3=moderate, 4=severe.

d

e

f

12.6 ± 4.5 (n=189)

159.1 ± 87.1 (n=154)

3.0 ± 0.5 (n=189)

Clinical summary 2018-04-01  English 13

Follow-up rate

A total of 38 sites in the United States enrolled subjects in the study. In total, 571
subjects were enrolled (243 randomized cohort, 328 not randomized) between
2007-2010. In the randomized cohort, 147 subjects were randomized with 70 to SNM
and 77 to CMM. Patients in both randomization arms were followed at 3 months and 6
months. In the all implanted cohort, 340 subjects went through test stimulation with the
lead (114 randomized cohort, 226 not randomized) and 272 patients were implanted
with a full system (91 randomized cohort, 181 not randomized). Patients were followed
at 3, 6, 12, 24, 36, 48, and 60 months post-implant.

Table 3 describes the follow-up rate for the randomized cohort at 6 months. The follow­up period for the randomized cohort was 2007 to 2011.

Table 3. Follow-up rate for randomized cohort at 6 months

SNM (n=70) CMM (n=77)

Not implanted Fully implanted

a

Theoretically Due

19 51 77

Actual 9 50 70

% Follow-Up

a

Number of subjects who would have been eligible for follow-up according to date of follow-up and
follow-up schedules.

b

Percent follow-up=Actual/Theoretically Due.

Table 4 describes the follow-up rate for all-implanted patients. The follow-up period for
the all-implanted cohort was 2007 to 2016.

b

47% 98% 91%

Table 4. Follow-up rate for all-implanted patients.

12 months 5 years

Theoretically Due

a

272 272

Actual 248 169

% Follow-Up

a

Number of subjects who would have been eligible for follow-up according to date of follow-up and
follow-up schedules.

b

Percent follow-up=Actual/Theoretically Due.

b

91% 62%

Final study results, randomized cohort

In the randomized cohort, a total of 243 subjects were enrolled, of which 96 subjects
were screen failures and were not randomized. The remaining 147 subjects were
randomized, with 70 to SNM and 77 to CMM. Efficacy, adverse events, and QOL for

14 English  Clinical summary 2018-04-01

the randomized groups were evaluated and compared at 6 months after
randomization.

Efficacy

Diary results from the intent-to-treat analysis demonstrated that the primary objective
of OAB success rate was greater at 6 months for the SNM group (61%) than the CMM
group (42%), as shown in Table 5. This difference was statistically significant
(p=0.016). Similar findings were demonstrated in the as-treated analysis, with OAB
success rates of 76% for SNM compared to 49% for CMM (p=0.002). These data
support the primary hypothesis that SNM is superior to CMM in the treatment of OAB.
Based on the as-treated analysis, for subjects with UI at baseline, 71% of SNM
subjects demonstrated therapeutic success as compared to 47% of CMM subjects
(p=0.034). The rate of complete continence was nearly doubled in the SNM group
(39% vs. 21%), and this trended towards statistical significance (p=0.06). For subjects
with UF at baseline, 61% of SNM subjects achieved therapeutic success as compared
to 37% of CMM subjects (p=0.043).

Table 5. Therapeutic success rates at 6 months for SNM vs CMM

Urinary
condition

Intent-to-treat analysis As-treated analysis

SNM CMM p-

n Success

rate

n Success

rate

value

SNM CMM p-

a

n Success

rate

n Success

rate

value

OAB 70 61% 77 42% 0.016 51 76% 73 49% 0.002

UI 51 59% 61 39% 0.057 38 71% 57 47% 0.034

UF 45 47% 50 32% 0.206 33 61% 46 37% 0.043

a

P-values for OAB success rate were from Cochran-Mantel-Haenszel test; p-values for UI and UF
success rates were from Fisher’s exact test.

Adverse events

Device-related adverse events related to surgery, therapy, device or implant site
occurred in 30.5% (18/59) of subjects with a lead implant and none were serious. The
most common device-related AEs in SNM subjects were undesirable change in
stimulation (10.2%, 6/59), implant site pain (8.5%, 5/59), lead migration/dislodgment
(3.4%, 2/59), and implant site infection (3.4%, 2/59). These events did not occur in the
CMM group because subjects did not receive neurostimulation. OAB medication­related events occurred in 27.3% (21/77) of CMM subjects and none were serious. The
three most common medication-related AEs in CMM subjects were constipation (9.1%,
7/77), drug toxicity (6.5%, 5/77), and dry mouth (5.2%, 4/77). The serious AE rates in
both groups were low: 8.5% (5/59) in SNM and 6.5% (5/77) in CMM.

Comparisons were made between 51 SNM subjects with full system implant and 75
CMM subjects without an implant. Between randomization and the 6-month data cutoff,
the three most common non-therapy related adverse events are as follows. For SNM

a

Clinical summary 2018-04-01  English 15

subjects with a full system implant: urinary tract infection (21.6%, 11/51),
nasopharyngitis (7.8%, 4/51), and sinusitis (7.8%, 4/51). These were also the most
common non-therapy related adverse events for CMM subjects with no implant: urinary
tract infection (5.3%, 4/75), nasopharyngitis (2.7%, 2/75), and sinusitis (2.7%, 2/75). In
addition, other events in this group of subjects occurred at a rate of 2.7% (2/75)
including upper respiratory tract infection, pain, hypersensitivity, nausea, and viral
infection.

For the 51 SNM subjects with full system implant, the 6-month post-implant surgical
intervention rate was 3.9% (2/51), with 2.0% (1/51) for device revision and 2.0% (1/51)
for device explant. Surgical procedures to resolve adverse events or technical
observations, or due to lack of efficacy were reported for 6 subjects (11.8%) from the
time of test lead implant to 6-month follow-up after full system implant.

Quality of life results

To evaluate improvements in QOL, patients completed questionnaires that measured
the impact of overactive bladder symptoms on quality of life, sexual matters,
depression, and pelvic pain associated with urgency. Comparisons were made
between SNM and CMM in various measures for QOL at 6 months after
randomization. Results were reported from the analyses based on the treatment that
patients received (as-treated).

As shown in Figure 1, HRQL and its 4 subscales in the ICIQ-OABqol showed greater
improvement in the SNM group compared to the CMM group (all p<0.001)

6

.

6

Minimally Important Difference (MID) is the smallest score change that is perceived beneficial to
patients and is often used to determine whether changes in scores are considered clinically
significant (Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the
minimal clinically important difference. Controlled Clinical Trials 1989;10:407-15.).
The MID for the OABqol subscales has been suggested to be 10 points (Coyne KS, Matza LS,
Thompson CL, Kopp ZS, Khullar V. Determining the importance of change in the overactive
bladder questionnaire. J Urol. 2006 Aug; 176(2): 627-32.).

16 English  Clinical summary 2018-04-01

Figure 1. Results of ICIQ-OABqol score improvement at 6 months from baseline, as-

One of the questions included in the OABqol asked, “Overall, how much do your
urinary symptoms interfere with your everyday life?” This was measured on a scale
from 0-10, and a lower score was indicative of less interference. It provides an overall
assessment of how subjects feel about the OAB symptom interference at each
scheduled visit. Based on the difference between scores at 6 months and baseline,
each subject is categorized as worsened, no change, improved, or greatly improved.

Figure 2 shows that 86% of SNM subjects reported improved or greatly improved
urinary symptom interference score at 6 months, compared to 44% for CMM subjects.
No SNM subject reported worsened urinary symptom interference.

treated analysis

Clinical summary 2018-04-01  English 17

Figure 2. Results of ICIQ-OABqol – urinary symptom interference improvement at 6

Results for the remaining quality of life measures are shown in Table 6. At 6 months,
compared to the CMM group, the SNM group had a greater improvement in sexual
matters (p=0.026 for males and p=0.0498 for females), and a greater improvement in
depression as measured by the BDI-II (p=0.011). There was no statistically significant
difference between the SNM group and the CMM group in pelvic pain at 6 months.

18 English  Clinical summary 2018-04-01

months, as-treated analysis

Table 6. Quality of life results at 6 months, as-treated analysis

QOL
measures

n Baseline

b

b

46.00

b

46 6.13

51 13.4

50 2.54

b

MLUTSsex

FLUTSsex

BDI-II

VAS for
pelvic pain

a

A negative change indicates improvement in quality of life over time.

b

MLUTSsex/FLUTSsex =Male/Female Lower Urinary Tract Symptom sexual function questionnaire,
BDI-II=Beck Depression Inventory-II, VAS=Visual Analog Scale

c

Within group change from baseline, Wilcoxon signed-rank test p<0.05.

SNM CMM p-

Month

Mean

±std

± 2.94

± 4.10

± 11.7

± 3.15

6

Mean

±std

4.25

± 2.75

4.63

± 4.35

6.6

± 7.2

1.32

± 2.04

Change

± 0.96

± 4.68

± 10.2

± 3.01

Mean

±std

-1.75

-1.50

-6.7

-1.21

n Baseline

46.00

67 5.66

c

77 11.4

c

76 2.72

c

Mean

±std

± 2.45

± 3.50

± 9.3

± 2.88

Month

6

Mean

±std

6.25

± 2.50

5.67

± 3.71

9.3

± 8.1

2.42

± 2.70

Change

Mean

±std

0.25

± 0.50

0.01

± 3.83

-2.1

± 7.2

-0.30

± 2.57

a

value

0.026

0.0498

0.011

c

0.060

Administered treatments

This section describes the treatments received by each randomization group. In the
SNM group, the neurostimulator was programmed by the physician following full
system implant and there were no protocol-specified programming requirements. Out
of 47 patients with programming parameters, most patients had programmed
amplitude of less than 4 volts (n=37, 79%), a pulse width of 210 µsec (n=32, 68%), a
rate between 14 hz and 18 hz (n=41, 87%), and had cycling turned off (n= 31, 66%).

In the CMM group, nearly all patients (96.1%) used OAB medication (anticholinergics
or antimuscarinics) at some time during the 6-month data period. In many cases,
patients used more than 1 medication during the follow-up period, with 1 patient using
6 different medications. Approximately 70% of patients were using medications on at
least 4 out of every 5 days (80% usage) while only a small percentage (14%) of
patients were using medications 30% of the time or less.

Concomitant therapy use

For SNM patients who received the full system implant, 3.9% (2/51) used OAB
medications between test stimulation and the 6-month follow-up, which was reported
as a protocol deviation. Overall, 12.5% (16/128) of subjects reported any use of
concomitant non-pharmacologic therapies, with 13.7% (7/51) of SNM subjects with full
system implant and 11.7% (9/77) of CMM subjects receiving such therapies.

Clinical summary 2018-04-01  English 19

Tined lead removal

Through the 6-month data cutoff, 18 patients had 21 tined leads explanted (13 leads
explanted before the neurostimulator implant date, 7 leads explanted on the
neurostimulator implant date and 1 lead explanted after neurostimulator implant).
Fifteen patients had 1 tined lead explanted (total explanted tined leads = 15) and 3
patients had 2 tined leads explanted (total explanted tined leads = 6).

The majority of lead removals had no difficulty (95.2%, 20/21). For one patient the lead
was removed 14 days after lead implant due to unsuccessful test stimulation with
gentle traction but moderate difficulty (significant fibrosis requiring more than one
incision for removal). There was no trauma associated with this lead removal.

The majority of lead removals had no trauma (95.2%, 20/21). For one patient the lead
was removed due to an adverse event of lead migration/dislodgement. The lead was
removed 14 days after the lead implant with gentle traction without difficulty. Mild
trauma (some bleeding/hematoma/multiple attempts same side) was associated with
lead removal.

Final study results, all-implanted cohort

The all-implanted cohort included implanted subjects from the initial randomized cohort
plus additional subjects enrolled in the study after the randomized cohort enrollment
was complete. In total, 340 subjects went through test stimulation, out of which 272
subjects received a full InterStim system implant including 51 subjects randomized to
SNM, 40 subjects initially randomized to CMM, and an additional 181 subjects who
were not randomized. Adverse events, therapy effectiveness, and QOL were evaluated
for all implanted subjects at 12 months and 5 years.

Adverse events

Device-related adverse events occurred in 16% (56/340) of subjects with lead implant
during test stimulation and in 30% (82/272) of subjects with full system implant
between neurostimulator implant and the 12-month cut off. The total device-related
adverse event rate for all patients who received a lead implant through the 12-month
data cutoff was 35% (119/340). The total device-related adverse event rate for all
patients who received a lead implant through the 5-year follow-up was 55% (188/340).
Three device-related events during test stimulation and 1 event after neurostimulator
implant were serious (test stimulation: implant site infection, skin infection, and
respiratory arrest; post implant: implant site erosion). All events were resolved.

Staged implant test stimulation adverse events

During test stimulation, implant site infection was the most common device-related
adverse event (9 events occurring in 3% [9/340] of patients), followed by implant site

20 English  Clinical summary 2018-04-01

pain (6 events in 2% [6/340]), lead migration/dislodgement (5 events in 1% [5/340]),
and undesirable change in stimulation (5 events in 1% [5/340]).

Table 7. Device- or therapy-related adverse events during test stimulation

Adverse events preferred term Number of events

Implant site infection 9 9 (3%)

Implant site pain 6 6 (2%)

Lead migration/dislodgment 5 5 (1%)

Undesirable change in
stimulation

Extension fracture 4 4 (1%)

Back pain 2 2 (< 1%)

Incision site complication 2 2 (< 1%)

Implant site erythema 2 2 (< 1%)

Implant site hemorrhage 2 2 (< 1%)

Paresthesia 2 2 (< 1%)

Pelvic pain 2 2 (< 1%)

Wound dehiscence 2 2 (< 1%)

Anal discomfort 1 1 (< 1%)

Arthralgia 1 1 (< 1%)

Change in sensation of
stimulation

Dermatitis 1 1 (< 1%)

Dermatitis contact 1 1 (< 1%)

Fungal skin infection 1 1 (< 1%)

Hematoma 1 1 (< 1%)

Hypersensitivity 1 1 (< 1%)

Implant site cellulitis 1 1 (< 1%)

Implant site discharge 1 1 (< 1%)

Incisional drainage 1 1 (< 1%)

Pain in extremity 1 1 (< 1%)

(cumulative)

55 (1%)

11 (< 1%)

Number (%) of patients

(cumulative)

(n=340)

Clinical summary 2018-04-01  English 21

Table 7. Device- or therapy-related adverse events during test stimulation

Adverse events preferred term Number of events

Post procedural complication 1 1 (< 1%)

Post procedural discomfort 1 1 (< 1%)

Post procedural pain 1 1 (< 1%)

Pruritus 1 1 (< 1%)

Respiratory arrest 1 1 (< 1%)

Skin infection 1 1 (< 1%)

Skin reaction 1 1 (< 1%)

Staphylococcal infection 1 1 (< 1%)

Surgery 1 1 (< 1%)

Total 64 56 (16%)

(continued)

(cumulative)

Number (%) of patients

(cumulative)

(n=340)

12-month follow-up results

Post-neurostimulator implant adverse events

Post full-system implant up through the 12-month data cutoff, undesirable change in
stimulation was the most common device-related adverse event (36 events occurring
in 12% [32/272] of subjects), followed by implant site pain (26 events in 7% [20/272])
and implant site infection (12 events in 3% [9/272]).

Over half (56%) of the device-related adverse events reported post-implant occurred
between implant and the 3-month visit.

Post full-system implant through the 12-month data cutoff, the most common non­therapy-related adverse events were: urinary tract infection (14%, 38/272), back pain
(4%, 12/272), and upper respiratory tract infection (4%, 11/272).

22 English  Clinical summary 2018-04-01