Overactive Bladder, Urinary Incontinence, Urgency-frequency
Conditions
Keywords
overactive bladder, urinary incontinence, incontinence,Urgency-frequency
Brief summary
The purposes of this study are: 1. To provide evidence from a randomized controlled trial that InterStim Therapy provides better relief of symptoms of OAB than standard medical treatments in current use. 2. To fulfill the requirements of the FDA-mandated post-approval study of the safety of the tined lead using a minimally invasive approach.
Detailed description
Approximately 30 million Americans meet the criteria for overactive bladder (OAB). Urinary voiding dysfunction symptoms impose a significant physical and psychosocial impact on individuals, including loss of self-esteem and a decrease in the ability to maintain an independent lifestyle. These symptoms can substantially affect a subject's daily activities. Patients with OAB are managed with diet modification, bladder training or retraining, pelvic muscle rehabilitation, medication and biofeedback. Medications are used as the first-line therapy for urgency frequency and urinary urge incontinence. InterStim Therapy utilizes sacral nerve stimulation and is indicated in the US for the treatment of urinary retention and the symptoms of OAB, including urinary urge incontinence and significant symptoms of urgency-frequency alone or in combination, in subjects who have failed or could not tolerate more conservative treatments. InSite OAB Protocol 1634 consists of two phases; Phase I which is the randomized portion of the trail and Phase II the non-randomized portion. Phase 1: A minimum of 60 subjects randomized to InterStim and a minimum of 60 subjects randomized to SMT. Phase 2: Non-randomized, all qualified subjects will receive InterStim, approximately 297 enrolled Subjects previously enrolled in Protocol 1634 for Urinary Urge Incontinence and Protocol 1635 for Urgency-Frequency will be included in Phase I of the new Protocol 1634 of OAB.
Interventions
DEVICEInterStim
DRUGStandard Medical Therapy
Oxybutynin 2.5mg, 5mg Oxybutynin extended release 5 mg, 10mg, 15mg Oxybutynin transdermal 3.9mg Solifenacin 5mg, 10mg Tolterodine 1mg, 2mg Tolterodine extended release 2mg, 4mg Trospium 20mg Darifenacin extended release 7.5mg, 15mg fesoterodine Fumarate 4mg, 8mg
Sponsors
MedtronicNeuro
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of OAB including urinary urge incontinence or urgency-frequency * Be male or female at least 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 are not a candidate for more conservative treatment (e.g. 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 one anticholinergic or antimuscarinic medication AND have at least one anticholinergic or antimuscarinic medication not yet attempted * Have been on current regiment of OAB medications or have not been on any OAB medications, for at least 4 weeks prior to beginning the baseline voiding diary
Exclusion criteria
* Have severe or uncontrolled diabetes or diabetes with peripheral nerve involvement * Have concomitant medical conditions which would limit the success of the study procedure * Have skin, orthopedic or neurologic anatomical limitations that could prevent successful placement of an electrode * Have neurological diseases such as multiple sclerosis, clinically significant peripheral neuropathy or complete spinal cord injury (e.g., paraplegia) * Have knowledge of planned MRIs, diathermy, microwave exposure, high output ultrasonic exposure, or RF energy exposure * Have urinary tract mechanical obstruction such as benign prostatic hypertrophy, cancer, or urethral stricture * Have symptomatic urinary tract infection (UTI) * Have implantable neurostimulators, pacemakers, or defibrillators * Have primary stress incontinence or mixed incontinence where the stress component overrides the urge component * Have had treatment of urinary symptoms with botulinum toxin therapy in the past 12 months * Be a woman who is pregnant or planning to become pregnant or are a woman of child-bearing potential who is not using a medically-acceptable method of birth control * Have a life expectancy of less than one year * Have plans to enroll in another investigation device or drug trial during their participation in this trial, or currently enrolled in an investigational device or drug trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Cohort: OAB Therapeutic Response | 6 months | To demonstrate that the OAB therapeutic response rate at 6 months is greater for the InterStim therapy group than for the Standard Medical Therapy group. OAB therapeutic response rate was calculated as number of subjects with OAB therapeutic response divided by number of subjects included in the analysis. OAB therapeutic response was defined as: * at least 50% or greater improvement in average leaks/day from baseline for subjects 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 subjects with urgency-frequency at baseline. |
| All Implanted Cohort: Adverse Events Related to the Tined Lead That Require Surgery | 5 years | To demonstrate that the upper bound of the 95% CI for the cumulative five-year rate of adverse events related to the tined lead that require surgery is less than 0.33. Adverse events on or after neurostimulator implant with an etiology of lead and with an intervention of surgical intervention/revision are the event of interest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Implanted Cohort: Tined Lead Migration Rate | 5 years | To estimate the suspected cumulative tined lead migration rate at 5 years in subjects with a full system implant. Suspected tined lead migration resulting in an adverse event of lead migration/dislodgement meets the definition of this endpoint. |
| All Implanted Cohort: Infection Rate Associated With the Tined Lead | 5 years | To characterize the cumulative infection rate at 5 years associated with the tined lead in subjects with a full system implant. |
Participant flow
Recruitment details
Thirty-eight centers were activated to enroll subjects. In total, 571 subjects were enrolled: 243 randomized cohort (96 excluded due to eligibility failure); 328 non-randomized cohort (102 excluded due to declined to participate; did not meet inclusion criteria and other). Subjects were enrolled between November 2007 and March 10, 2011.
Pre-assignment details
The study has 2 cohorts. The randomized cohort included subjects who were randomized 1:1 to either InterStim Therapy (IST) or Standard Medical Therapy (SMT) and were followed for 6 months. The all implanted cohort include implanted subjects from the randomized cohort plus additional subjects enrolled after randomized cohort enrollment completion.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Cohort: InterStim Therapy This includes those subjects who were randomized to InterStim Therapy. | 70 |
| Randomized Cohort: Standard Medical Therapy This includes subjects who were randomized to Standard Medical Therapy. After being followed at SMT Month 6, these subjects could choose to receive test stimulation and if successful, received full system implant. | 77 |
| All Implanted Cohort: Non-randomized Subjects These additional subjects were not randomized. These non-randomized subjects went through test stimulation and, if successful, were implanted with the InterStim Therapy system. | 181 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| All Implanted Cohort | Adverse Event | 4 | 10 | 17 |
| All Implanted Cohort | Death | 3 | 1 | 4 |
| All Implanted Cohort | Lost to Follow-up | 0 | 1 | 14 |
| All Implanted Cohort | Other reasons | 1 | 0 | 1 |
| All Implanted Cohort | Physician Decision | 0 | 2 | 6 |
| All Implanted Cohort | Site closure | 2 | 0 | 1 |
| All Implanted Cohort | Withdrawal by Subject | 5 | 4 | 27 |
| Randomized Cohort | Adverse Event | 1 | 0 | 0 |
| Randomized Cohort | Death | 0 | 1 | 0 |
| Randomized Cohort | Lost to Follow-up | 1 | 0 | 0 |
| Randomized Cohort | Other reasons | 2 | 0 | 0 |
| Randomized Cohort | Withdrawal by Subject | 7 | 5 | 0 |
Baseline characteristics
| Characteristic | Randomized Cohort: Standard Medical Therapy | All Implanted Cohort: Non-randomized Subjects | Randomized Cohort: InterStim Therapy | Total |
|---|---|---|---|---|
| Age, Customized Age, years | 57.1 years STANDARD_DEVIATION 15.3 | 57.2 years STANDARD_DEVIATION 14.1 | 60.4 years STANDARD_DEVIATION 14.4 | 57.9 years STANDARD_DEVIATION 14.5 |
| Baseline Leaks/Day | 2.7 Leaks/Day STANDARD_DEVIATION 1.9 | 3.4 Leaks/Day STANDARD_DEVIATION 3 | 2.4 Leaks/Day STANDARD_DEVIATION 1.7 | 3.0 Leaks/Day STANDARD_DEVIATION 2.6 |
| Baseline Voids/Day | 11.9 Voids/Day STANDARD_DEVIATION 4.3 | 13.1 Voids/Day STANDARD_DEVIATION 4.8 | 11.2 Voids/Day STANDARD_DEVIATION 2.9 | 12.5 Voids/Day STANDARD_DEVIATION 4.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 8 Participants | 3 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 173 Participants | 67 Participants | 317 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native/White | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian/White | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black | 7 Participants | 12 Participants | 7 Participants | 26 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Race White | 70 Participants | 161 Participants | 61 Participants | 292 Participants |
| Sex: Female, Male Female | 71 Participants | 165 Participants | 66 Participants | 302 Participants |
| Sex: Female, Male Male | 6 Participants | 16 Participants | 4 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 1 / 75 | 8 / 272 |
| other Total, other adverse events | 29 / 51 | 22 / 75 | 217 / 272 |
| serious Total, serious adverse events | 5 / 51 | 4 / 75 | 107 / 272 |
Outcome results
Primary
All Implanted Cohort: Adverse Events Related to the Tined Lead That Require Surgery
To demonstrate that the upper bound of the 95% CI for the cumulative five-year rate of adverse events related to the tined lead that require surgery is less than 0.33. Adverse events on or after neurostimulator implant with an etiology of lead and with an intervention of surgical intervention/revision are the event of interest.
Time frame: 5 years
Population: This objective was analyzed in the all implanted cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| InterStim Therapy | All Implanted Cohort: Adverse Events Related to the Tined Lead That Require Surgery | 0.224 Cumulative probability at 5 years |
Primary
Randomized Cohort: OAB Therapeutic Response
To demonstrate that the OAB therapeutic response rate at 6 months is greater for the InterStim therapy group than for the Standard Medical Therapy group. OAB therapeutic response rate was calculated as number of subjects with OAB therapeutic response divided by number of subjects included in the analysis. OAB therapeutic response was defined as: * at least 50% or greater improvement in average leaks/day from baseline for subjects 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 subjects with urgency-frequency at baseline.
Time frame: 6 months
Population: Intent-to-Treat (ITT): an analysis that includes all randomized subjects. This was analysis in the randomized cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| InterStim Therapy | Randomized Cohort: OAB Therapeutic Response | 61 percentage of participants with response |
| Standard Medical Therapy | Randomized Cohort: OAB Therapeutic Response | 42 percentage of participants with response |
p-value: 0.016Cochran-Mantel-Haenszel
Secondary
All Implanted Cohort: Infection Rate Associated With the Tined Lead
To characterize the cumulative infection rate at 5 years associated with the tined lead in subjects with a full system implant.
Time frame: 5 years
Population: This objective was analyzed in the all implanted cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| InterStim Therapy | All Implanted Cohort: Infection Rate Associated With the Tined Lead | 0.012 Cumulative probability at 5 years |
Secondary
All Implanted Cohort: Tined Lead Migration Rate
To estimate the suspected cumulative tined lead migration rate at 5 years in subjects with a full system implant. Suspected tined lead migration resulting in an adverse event of lead migration/dislodgement meets the definition of this endpoint.
Time frame: 5 years
Population: This objective was analyzed in the all implanted cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| InterStim Therapy | All Implanted Cohort: Tined Lead Migration Rate | 0.059 Cumulative probability at 5 years |