SANUWAVE Health, Inc. (OTCBB:SNWV) (
www.sanuwave.com), today announced positive combined 24-week data from the Company’s pivotal double-blinded, randomized Phase III, Investigational Device Exemption (IDE) clinical trials comparing dermaPACE? to Sham-control (non-active treatment), when both are combined with the current standard of care for the treatment of diabetic foot ulcers. Diabetic foot ulcers are an area of significant unmet medical need and represent a $2 billion market in the U.S. alone.
The dermaPACE system was evaluated using two studies under an FDA approved IDE. The studies were designed as prospective, randomized, double-blind, parallel-group, sham-controlled, multi-center 24-week studies at 39 centers. A total of 336 subjects were enrolled and treated with either active dermaPACE plus conventional therapy or sham dermaPACE plus conventional therapy (a.k.a. standard of care). Conventional therapy included, but was not limited to, debridement, saline-moistened gauze, and pressure reducing footwear. The objective of the studies was to compare the safety and efficacy of the dermaPACE device to sham-control application. The prospectively defined primary efficacy endpoint for the dermaPACE studies was the incidence of complete wound closure at 12 weeks post-initial application of the dermaPACE system (active or sham). Complete wound closure was defined as complete skin re-epithelialization without drainage or dressing requirements, confirmed over two consecutive visits within 12-weeks. If the wound was considered closed for the first time at the 12 week visit, then the next visit was used to confirm closure. Investigators continued to follow subjects and evaluate wound closure through 24 weeks.
Summary of Key Findings from the Combined Study Data
The first trial showed that the dermaPACE treatment is safe and is well-tolerated by patients.
The second, supplemental trial validated these results. The overall percentage of adverse events reported during the studies was comparable between both study groups (p=0.338).
No adverse events were considered definitely related to treatment with the dermaPACE system.
The effectiveness results demonstrate superiority in wound closure of dermaPACE compared to the control at 20 and 24 weeks, as well as, the additional supporting analyses:
dermaPACE demonstrated superior results in wound closure at 20 and 24 weeks compared to the control ( 35.47% vs. 24.39%; p=0.027 at respectively at 20 weeks and 37.79% vs. 26.22%; p=0.023, respectively at 24 weeks)
dermaPACE demonstrated comparable results in wound closure at 12 weeks compared to the control (22.67% vs. 18.29%; p=0.320, respectively)
dermaPACE demonstrated superior results in the overall rate to wound closure compared to the control (p=0.0346) demonstrating that subjects are reaching wound closure at a faster rate when dermaPACE treatment is applied
dermaPACE demonstrated superior results in the reduction in area (cm2) of the wound when compared to the control at 24 weeks (1.92cm2 versus 0.16cm2; p=0.047, respectively).
dermaPACE demonstrated superior results in the prevention of wound expansion (≥ 10% increase in wound size) over the course of the study at 12 weeks (18.0% versus 31.1%; p=0.005, respectively)
dermaPACE demonstrated a trend toward superiority in the prevention of wound expansion (≥ 10% increase in wound size) over the course of the study at 24 weeks (25.6% versus 34.2%; p=0.086, respectively)
dermaPACE demonstrated a lower overall rate of full target ulcer amputations compared to the control (2.3% vs. 3.0%; p-value=0.745, respectively)
Clinical Studies Results
I. Primary Efficacy Analysis at 12 and 24 Weeks
In both studies, the primary endpoint was to assess the effectiveness (incidence of complete wound closure) of the dermaPACE and sham-control groups 12 weeks post-initial application. While superiority was not demonstrated at 12 weeks, superiority was demonstrated at 20 weeks and 24 weeks post-initial application.
While not statistically significant, the percentage of dermaPACE subjects with wound closure is higher at 12 weeks compared to the control. Although the primary endpoint was not met, these results do demonstrate a reasonable assurance of effectiveness at the later time points when using dermaPACE system.
Study 2 does not demonstrate superiority at these timepoints (p=0.339 and p=0.254, respectively), the overall population indicates that the device does offer a benefit to patients at a very low risk. The wound closure rate for dermaPACE at 24 weeks in Study 2 was 35.4% compared to 26.2% in the sham control.
On a combined basis, at the 12 week endpoint a total of 39 out of 172 (22.7%) of dermaPACE patients had complete wound closure, compared to 30 out of 164 (18.3%) in the control group. There was no statistically significant difference in wound closure at the 12 week follow up between the dermaPACE and control group; however, in subsequent visits a trend towards significance was shown resulting in a significant difference by the 20 week endpoint that was maintained through the end of the study. At the 24 week endpoint, the rate of wound closure in the dermaPACE cohort was 37.8% compared to 26.2% for the control group, resulting in a p-value of 0.023
In Time-to-Closure analysis on the combined study data, the proportion of patients with wound closure indicate a statistically significant difference between the dermaPACE and the control group in the proportion of subjects with the target-ulcer not closed over the course of the study (p-value=0.0346).
Approximately 25% of dermaPACE subjects reached wound closure per the study definition by day 84 (week 12). The same percentage in the control group (25%) did not reach wound closure until day 112 (week 16). These data indicate that in addition to the proportion of subjects reaching wound closure being higher in the dermaPACE group, subjects are also reaching wound closure at a faster rate when dermaPACE is applied.
II. Additional Efficacy Analyses
A number of additional analyses were conducted on the combined study data to support the conclusion that dermaPACE provides a reasonable assurance of safety and effectiveness when used to treat diabetic foot ulcers.
An analysis was performed on subjects who had a 50% wound area reduction maintained at two consecutive visits. At 12 and 24 weeks, the dermaPACE group has a higher percentage of subjects with a 50% wound reduction compared to control (p=0.0554 and p=0.0899, respectively). Both time points demonstrate a trend toward statistical significance.
The mean wound area reduction for both cohorts was analyzed and the mean wound reduction for dermaPACE subjects at 24 weeks was 1.92cm2 compared to 0.16cm2 in the control group. There was a statistically significant difference between the wound area reductions of the two cohorts from the 6 week follow up visit through the end of the study. Because means can be influenced by outliers in the data, the median wound reduction was also reported and favored dermaPACE system.
An analysis on the number of patients reporting an increase in wound size demonstrates that a significantly greater proportion of sham control subjects had an increase of at least 10% in their wound area. This indicates that not only does dermaPACE aid in wound healing (decrease in wound size), dermaPACE also may prevent wounds from getting worse (increasing in wound size). The differences are statistically significant in favor of dermaPACE with the exception of Week 2 and Week 24 which are both trending towards significance.
The success results at 12 and 24 weeks have been stratified by demographic characteristics to determine if any notable differences were identified when each characteristic is compared.
At 12 weeks, the only statistically significant difference observed between the two groups was in the subjects who were greater than or equal to 70 inches in height. The percentage of dermaPACE subject who had complete wound closure was 30.0% compared to 14.1% in the control group.
At 24 weeks, several sub-populations demonstrated a statistically higher percentage of wound closure in dermaPACE subjects compared to the control subjects. Subjects with age less than 65 years, BMI less than 32, height greater than or equal to 70 inches, and male subjects all had success rates statistically significantly higher than the control group (p-value = ≤ 0.050).
III. Safety
The primary safety endpoint of the overall rate of adverse events throughout the 24 week study was not statistically different between dermaPACE and Sham-control. The total number of serious adverse events related to application site infections was reduced in dermaPACE and no issues regarding the tolerability of dermaPACE treatment was shown throughout the application, treatment and follow-up periods of the study.
In addition to a lower rate of serious adverse events, the dermaPACE cohort exhibited a lower rate of target ulcer recurrence and amputations.
The recurrence rate for dermaPACE patients was 7.7% compared to 11.6% in the control group (p-value=0.490). The percentage of patients that had to undergo amputation of the target ulcer was lower in dermaPACE as well (2.3% vs. 3.0%, p-value= 0.745, respectively).
Kevin Richardson, Chairman and CEO of SANUWAVE Health, Inc. stated, “The dermaPACE device demonstrates a positive benefit-risk ratio based on the outcome of the two clinical studies performed. A significantly greater percentage of dermaPACE subjects were considered a success at 20 weeks and out to final follow-up at 24 weeks. While, the data did not demonstrate superiority at 12 weeks, a trend is clearly demonstrated toward superior effectiveness when using dermaPACE to treat diabetic foot ulcers.”
Conclusions
Compared to the control, the dermaPACE data demonstrates a greater reduction in wound size and a lower number of subjects with an increase in wound size. As such, dermaPACE could be a factor in reducing the risks of infections, amputation and comorbidities associated with diabetic foot ulcers, improving the patient’s quality of life. In addition, the adverse events associated with the dermaPACE treatment were comparable to those seen in the control group in both incidence and type. These events are most likely a result of the diabetes or the foot ulcer rather than the actual dermaPACE device treatment.
It is important to note that a key benefit of the dermaPACE device is that it can be used in conjunction with standard of care or other treatment options as an initial alternative to more invasive, higher risk devices. If the physician feels that additional modes of treatment are needed in addition to dermaPACE, all other previously available treatment options are still available to the patient. In essence, the dermaPACE device provides an additional treatment option for clinicians to utilize, while not limiting any future or concurrent treatment options.
With CE Marking for dermaPACE in the European Union, and distribution approval in South Korea, Canada, Australia, New Zealand, and various other countries, dermaPACE is becoming a desired mode of treatment for DFUs on a growing global basis. Doctors and patients have been pleased with the accelerated wound area reduction and wound closure seen when using the device. The ease of treatment delivery is a key benefit for treating clinicians and the tolerability of the treatment is a welcome element for patients. The approval of dermaPACE by the FDA will improve our distribution efforts in these countries and assist with approval into new countries.
Next Steps
SANUWAVE has submitted a Pre-Submission package to FDA, detailing the results presented above.
We expect to meet face-to-face with the FDA review team in late-April or early-May.
The goal of this meeting is to work interactively with FDA to bring dermaPACE to market in the most expeditious possible manner.
Attending this meeting will be SANUWAVE’s regulatory consultants and Musculoskeletal Clinical Regulatory Advisors (MCRA).
MCRA is the world leading regulatory advisor to the neuro-musculoskeletal industry on U.S. FDA related activities.
Their expertise in helping companies gain FDA approval for products will benefit the Company greatly in representing dermaPACE to FDA.
The Company anticipates a final product submission to FDA in Q2 2016.
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