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VIVE: Compelling SUI Feasibility Study 6-Month Data. SUI LIBERATE RCTs On-Deck

By Brian Marckx, CFA



Last week Viveve (NASDAQ:VIVE) announced what we would characterize as potentially compelling 6-month data from its ongoing SUI 12-month feasibility study. As a refresher, this is the second formal pilot/feasibility study assessing the Viveve System in the treatment of mild-to-moderate SUI (see below for refresher on the first). Listed under Identifier: NCT03066180, the single-arm, 36-subject study is being conducted at Dr. Bruce Allan’s Allan Centre (Dr. Allan was also the principal investigator for the VIVEVE I vaginal laxity/sexual function study) in Calgary, Canada. Protocol allowed for one (just following baseline) or two (6 – 12 weeks later) Viveve treatments.

While only a single-arm feasibility study, it was clearly designed to be consistent with FDA's recommendations for SUI-device pivotal studies (FDA's guidance for Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence). This includes the inclusion and exclusion criteria as well as the choice of primary and secondary endpoints. Relative to SUI severity, inclusion criteria included diagnosis of mild-to-moderate SUI as determined by one-hour pad weight test (using International Continence Society definitions; mild = 1-10g, moderate = 11-50g, severe = > 50g).

Primary endpoint is reduction in 1-hour pad weight versus baseline. Secondary measures are the 7-day bladder voiding diary and composite scores from three quality-of-life oriented questionnaires; UDI-6 (Urogenital Distress Inventory-Short Form), IIQ-7 (Incontinence Impact Questionnaire) and ICIQ-UI-SF (International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form).

Results: 83% Response Rate on Primary Endpoint, 73% Average Reduction of Urine Leakage…

Of the 36 enrolled participants, 28 completed full follow-up (i.e. were assessed on all endpoints) through 6 months and one completed full follow-up except for the 7-day voiding diary through 6 months. Management mentioned on the call that while the two-treatment protocol was used with a few women, that there was not an obvious difference in efficacy as compared to a single treatment (a single treatment will be employed in upcoming studies). Results, which are also in the table below (from VIVE's press release), were;

1-hour pad weight test: the 1-hour pad weight test is also expected to serve as the primary endpoint in the two anticipated upcoming SUI LIBERATE studies. As measured by the 1-hour pad weight test (i.e. primary endpoint), average aggregate urine leakage decreased by 73% from baseline (6.2g vs 1.7g) and 83% (24 of 29) of women experienced improvement. For reference (and discussed in more detail below), FDA recommends (for the design of pivotal SUI studies) defining 'clinically meaningful improvement' as a reduction in urine leakage of 50% or more. Additionally (as it relates to the primary endpoint), 66% (19 of 29) of women met the clinically meaningful definition of 'dryness' - which is defined as urine leakage of one gram or less.

7-day voiding diary: the 7-day voiding diary, along with the 1-hour pad weight test, are two measures that FDA recommends using as primary endpoints for pivotal SUI device studies. Based on the 7-day voiding diary, VIVE's feasibility study showed that, through 6 months (n=28), average aggregate incontinence episodes decreased by 50% from baseline (2.0 vs 1.0) and 79% (22 of 28) of women experienced an improvement in incontinence episodes. For reference, FDA recommends defining 'clinically meaningful improvement' for the 7-day voiding diary as greater than 50% reduction in incontinence episodes compared to baseline. While VIVE did not report on 'dryness' as measured by the 7-day voiding diary (defined in our endpoints discussion below), that may be included in the 12-month data (which, potentially could be available late this year or early 2019).

QoL questionnaires: VIVE reported that, through 6 months, 'clinically meaningful' improvement was achieved on the composite scores of the three QoL questionnaires. Additionally, 69%, 83% and 86% of women reported improvement based on the IIQ-7, UDI-6 and ICIQ-UI-SF questionnaires. We discuss QoL measures for SUI device studies in more detail below.

View Exhibit I

Safety: as has largely been the case with Viveve treatment of vaginal laxity, there were no device-related adverse events through 6 months in this SUI feasibility study.

While, given this was a small single-arm study with data only through 6 months, we can not draw concrete conclusions in terms of efficacy . But, as management noted on the call, combined with positive data of the prior n=10 pilot study (see below), results to-date certainly appear to support the hypothesis that the Viveve system may have real clinical utility in improving SUI symptoms. Given that from a regulatory standpoint, efficacy through 12 months is what is important - we should know a lot more in terms of the potential utility of the Viveve system in SUI when 12-month results of this study are available.


In the meantime, VIVE anticipates making their IDE filing for LIBERATE U.S. in the very near-term - mentioning on the call that they expect to file by the end of June or early July. They also hope to have approval from Health Canada around the same time to begin the LIBERATE international study. At that time we should know the complete trial designs - including all endpoints. See our Appendix for refresher on both studies.

Relative to FDA's guidance on SUI endpoints…

◦ Primary endpoints: FDA recommends that a urinary incontinence device pivotal trial use one or both of the following measures as primary endpoints: urine leakage as assessed by pad weight test and/or reduction in the number of incontinence episodes per day. If only of the two is used as the primary endpoint, FDA further recommends using the other as a secondary endpoint
     • pad weight test: with the 1-hour pad weight test (which can also be performed over a 24-hour period), the subject wears a pre-weighed pad, drinks a specified amount of liquid and then performs certain activities (such as walking, climbing stairs, coughing etc). After one-hour, the pad is again weighed to determine the amount of urinary leakage. Relative to the what is considered clinically meaningful (with the objective on dryness) with the one-hour pad weight test, FDA recommends defining 'dryness' as an increase in pad weight of less than 1 gram and defining 'improvement' as a 50% or more decrease in weight from baseline

◦ Reduction in incontinence episodes: FDA recommends using a standardized voiding diary to document fluid intake and the number of incontinence episodes over seven consecutive days. The average number of incontinence episodes per day is then compared to baseline to determine effectiveness. With the 7-day voiding diary, FDA recommends using 'zero incontinence episodes per day' as the clinically meaningful definition of 'dryness' and 'greater than 50% reduction' (from baseline) as clinically meaningful improvement

◦ Secondary endpoints: FDA’s general guidance relative to stress urinary incontinence clinical trials is to choose secondary endpoints which will provide additional evidence of the efficacy and safety of the device as well as to support performance and labeling. Among the possible secondary endpoints, FDA recommends considering measures related to quality of life (via questionnaires), sexual function, leak point pressure, bladder voiding and patient satisfaction. Specifically as it relates to;

     • QoL: FDA's guidance notes that since UI "is strongly associated with impairment of quality of life," that they recommend using validated QoL measures (as secondary endpoints) such as the Incontinence Quality of Life (I-QOL) questionnaire (as an example of one of many QoL measures that could be employed) and pre-specify the minimum delta that represents a meaningful improvement in QoL. FDA's guidance further recommends that choice of QoL measures should consider the specific populations and settings where they were developed and validated. FDA references The 3rd International Consultation on Incontinence as a source for choosing appropriate QoL measures, which includes the three QoL measures used in VIVE's feasibility study (UDI-6, IIQ-7 and ICIQ-UI-SF). While we may have more discussion on the topic after we know specifics of design of the two LIBERATE studies, we think the most important take-away at this point is that the three QoL measures used in this ongoing feasibility study are definitely validated clinical endpoints

     ◦ Sexual function: based on close proximity to genitalia, FDA recommends consideration of a sexual function related measure (such as a validated sexual function questionnaire)

     ◦ Patient satisfaction: incorporate a validated patient satisfaction questionnaire which asks the participant to rate the improvement (as compared to baseline) on several topics related to how SUI effects their lives and livelihoods

SUI Market

According to the National Women's Health Resource Center (NWHRC), SUI is estimated to effect 30% of all adult women in the U.S. (i.e. ~31M Americans) and of those with SUI, 53% have "slight" incontinence while 17% have severe incontinence. SUI can be a significant hindrance to quality of life. The NWHRC reports that while 75% of women with the condition find it "bothersome" (or worse) and 60% make lifestyle changes as a result of it, as many as 50% to 75% of sufferers do not seek treatment (mostly as a result of embarrassment). SUI is more common among women that have had vaginal deliveries. We will expand on our discussion of the mild-to-moderate SUI market in future updates - hopefully corresponding to additional positive data from this ongoing 12-month feasibility study as well as the anticipated LIBERATE studies.

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