AOTI Ltd. (AOTI) would like to submit the following public comments to CMS for consideration relating to your National Coverage Analysis to consider Section C of NCD 20.29 (CAG-00060R).
We are delighted that CMS is reconsidering section C in NCD 20.29 (Topical Application of Oxygen) and that the focus of the reconsideration request will be the clinical efficacy of topical oxygen.
As your lead analyst has confirmed that this national coverage analysis applies to ALL topical applications of oxygen and not just the requestor’s continuous diffusion of oxygen therapy, we respectfully request that CMS also assess whether the use of AOTI’s unique patented Topical Wound Oxygen (TWO2) therapy in patients with chronic non-healing pressure ulcers, venous ulcers and diabetic foot ulcers is reasonable and necessary under Section 1862(a)(1)(A) or 1862(a)(1)(E) of the Social Security Act.
We agree with the requestor in that Topical Oxygen devices have evolved significantly since NCD 20.29 was published back in 2003. We also agree that there is extensive published “supportive science” evidence as to the overall mechanisms of action, physiological and metabolic response to oxygen applied topically in wound care, which is generally applicable to all Topical Oxygen approaches.  
However, it is also evident from a review of the FDA 510(k) Premarket Notification database for product code KPJ (Topical Oxygen Chamber for Extremities - 21CFR 878.5650) , that the cleared Topical Oxygen devices are not all the same either functionally or technologically. AOTI believes that there are three distinct approaches evident:
1. Continuous Diffusion of Oxygen Therapy (CDO) No Pressure Approach
The requestor’s TransCu 02 device and the Epiflo device from Neogenix fit into this category. These devices provide minute amounts of oxygen flow, around 0.00005 Liters Per Minute (LPM) via a cannula to an occlusive dressing applied over the ulcer area.
The lack of any positive pressure and very low oxygen flow rates of these devices appear not to allow for oxygen molecules to diffuse deep enough into the wound tissue in adequate quantities as to make meaningful clinical improvements to patient’s ulcers. This is evidenced by the non-significant primary outcome results from the Randomized Controlled Trials (RCTs) performed by each of the companies mentioned above. Both of these RCTs were in superficial Stage IA - University of Texas Classification of Diabetic Foot Ulcers, defined as “Superficial wounds, not involving tendon, capsule or bone, without infection or Ischemia”. 
Results for E02 Concepts’ TransCu O2 device RCT (ClinicalTrials.gov Identifier: NCT01645891) have yet to be published in their entirety, but interim results were published in a non-Medline listed peer reviewed journal that showed that; “wound closure at 12 weeks was not significantly associated with treatment per the protocol [Active 11 (52.3%), Sham 8 (38.1%), RR 1.38 (95% CI 0.7, 2.7), p = 0.54]”.  
Results for the Neogenix’s Epiflo device RCT (ClinicalTrials.gov Identifier: NCT01291160), have yet to be published in any journal, but results are available on clinicaltrials.gov, where you can see that wound closure at 12 weeks was not statistically significantly associated with treatment per the protocol [Active 61 (55.7%), Sham 61 (50.8%). 
2.Lower Constant Pressure approach
These devices are those that were predominately in the marketplace prior to the NCD 20.29 being published back in 2003 and include such devices as the O2 Boot by GWR Medical. In this approach oxygen is provided in a simple plastic chamber that is placed around the extremity with the ulcer. Constant pressure is then maintained within the chamber up to 22 mmHg.
There are numerous studies that have been conducted on these types of devices over that last four decades that have shown good clinical efficacy. However, the majority of these studies have consisted of case series or uncontrolled trials.  One RCT conducted back in 1988 and commonly cited by the Undersea and Hyperbaric Medical Society (UHMS) as to evidence as to the ineffectiveness of topical oxygen, is that from Leslie . This study was very underpowered and looked at differences in wound healing at only 2 weeks, concluding that “the size changes did not differ statistically between the control and therapy arm”. This outcome is not surprising considering the short two week duration of comparison and the fact that the therapy arm only received two treatments each week with the oxygen therapy devices utilized.
3. Higher Cyclical Humidified Pressure Approach
The Topical Wound Oxygen (TWO2) system by AOTI Ltd. is unique in that it is the only device that utilizes the third multi-modality approach, whereby an advanced plastic chamber is placed around the extremity with the ulcer. Oxygen is then delivered within the chamber at a 10 LPM flow rate to create pressure cycles between 5 mmHg and 50 mmHg. The oxygen is also combined with humidity to maintain an optimal wound healing environment. This approach is discussed in much greater detail in the comment following.
Comments regarding AOTI’s unique patented Topical Wound Oxygen (TWO2) therapy:
a. TWO2 Therapy Overview and Mechanisms of Action
Clinical evidence has continued to expand over the last five decades as to the importance of adequate tissue oxygen levels and the effect of low levels on non-healing wounds. It is clear that localized oxygen tensions in a chronic ulcer can be well below 10 mmHg and at such low levels multiple cellular mechanisms and enzymes are effectively turned off, contributing to the stalled non-healing wound paradigm.   Increased tissue oxygen levels are needed in all phases of wound healing to help combat infection, stimulate angiogenesis and produce effective collagen tissue.     There is also extensive published evidence that demonstrates that the oxygen imbalance seen in chronic wounds can be corrected either by systemic enhancement, as seen with full body Hyper Baric Oxygen (HBO) systems, or by localized topical delivery systems.   
AOTI’s patented application is called Topical Wound Oxygen (TWO2) and is unique to all others in that it is a multi-modality homecare therapy, that applies a higher topical oxygen pressure than that utilized with any other Topical Oxygen device, in a cyclical pressure waveform, combined with optimal moist wound healing humidity.  
The benefit of this approach is that the higher pressure gradient results in oxygen molecules diffusing deeper into the hypoxic wound tissue and enhance multiple molecular and enzymatic functions.    The availability to the wound tissue of higher partial pressures of oxygen reverses localized hypoxia, causing both the direct destruction of anaerobic bacteria and an upregulation in the wound tissue leukocyte function to address all other pathogens.    Once the inflammatory cascade subsides, the high availability of oxygen molecules in the wound tissue helps to upregulate VEGF and FGF-2 angiogenic growth factors  , resulting in the prolific structured growth of new blood vessels and the stimulation of collagen synthesis by enhancing fibroblast activity   . These factors combined result in better wound bed granulation, strong collagen tissue formation, and wound closure    .
The cyclical pressure applied with TWO2 of between 5 mmHg and 50 mmHg creates sequential non-contact compression of the limb consistent with that of compression dressings , that helps to reduce peripheral edema and stimulates wound site perfusion further.  
b. Summary of the Clinical Evidence for TWO2 therapy
The following table summarizes the leading published human clinical trial evidence as it relates specifically to AOTI’s TWO2 therapy in chronological order. The primary controlled clinical trials are then discussed in more detail after the table.
||No. of Patients
||Pressure & Diabetic
||Improved ulcer healing
Increased oxygen values in the peri-wound area
||Vascular and Endovascular Surgery
||Prospective Controlled Study
|| Mean reduction in ulcer surface area at 12 weeks 96% 76% of ulcers completely healed at 12 weeks. Median time to full healing was 57 days. Only 6% ulcer reoccurrence during 36 months follow-up.
||ISDF 2011 - 6th
International Symposium on the Diabetic Foot
|Randomized Controlled Trial
||Diabetic & Venous
||Diabetic ulcers 90% healed in 12 weeks.
Venous ulcers 50% healed in 12 weeks.
||Ostomy Wound Management
||Prospective Controlled Study
||82.4% of ulcers completely healed at 12 weeks.
Median time to full healing was 56 days.
No ulcer reoccurrence during 24 months follow-up.
|Tawfick & Sultan 
||European Journal of Vascular and Endovascular Surgery
||Prospective Controlled Study
||80% ulcers healed at 12 weeks.
Median time to full healing was 45 days.
No ulcer reoccurrence after 12 months follow-up.
Pain score improved from 8 to 3 by day 13.
|Japour C 
||European Wound Management Conference
||Average time to 100% closure was 3.4 months.
Average number of treatments to closure was 45
|Derk F 
||Desert Foot Conference Proceedings
||Diabetic & Dehiscence
||Average time to 100% closure was 12.7 weeks.
|Levine B 
||Desert Foot Conference Proceedings
||Diabetic & Venous
||Average time to 100% closure was 11.5 weeks.
Average number of treatments to closure was 33
|Edsberg L 
||Ostomy and Wound Management
||Healing of all wounds
|Fischer BH 
||Journal Dermatological Surgery
||Overall positive results
|Fischer BH 
Discussion on primary Controlled Clinical Studies on TWO2 therapy:
1. Technical and Clinical Outcome of Topical Wound Oxygen in Comparison to Conventional Compression Dressings in the Management of refractory Non-healing Venous Ulcers 
This controlled study looked at TWO2 therapy in the management of severe refractory non-healing venous ulcers (RVU) with the primary end points being the proportion of ulcers healed at 12 weeks, recurrence rates, reduction in ulcer size, and time to full healing.
A total of 132 patients were enrolled with 67 patients (mean age of 69 years) managed using TWO2 and 65 patients (mean age of 68 years) managed with conventional compression dressings (CCDs) for 12 weeks or until full healing.
The Key Results were:
1.1. Mean reduction in ulcer surface area at 12 weeks was 96% in patients managed with TWO2 and 61% in patients managed with CCD (P < .0001).
1.2. At 12 weeks 76% of the TWO2 managed ulcers had completely healed, compared to 46% of the CCD-managed ulcers (P < .0001).
1.3. Median time to full healing was 57 days in patients managed with TWO2 and 107 days in patients managed with CCD (P < .0001).
1.4. After 36 months follow-up, 47% of the healed CCD ulcers showed recurrence compared to only 6% of the TWO2 healed ulcers (P < .0001).
1.5. MRSA elimination occurred 46% patients managed with TWO2 and 0% patients managed with CCD (<.001).
1.6. Kaplan Meier curve of Time to Complete Healing:
IMAGE NOT AVAILABLE
2. Topical Wound Oxygen Therapy in the Treatment of Severe Diabetic Foot Ulcers: A Prospective Controlled Study 
This prospective controlled study was conducted to examine the clinical efficacy of TWO2 therapy in healing with severe Diabetic Foot Ulcer (DFU) patients referred for care to a community wound care clinic and were seen by an expert surgical team.
The primary endpoints were the proportion of ulcers healed at 12 weeks and the ulcer reoccurrence rates at 24 months.
The Key Results were:
2.1. At 12 weeks 82.4% of the ulcers in the TWO2 therapy arm and 45.5% in the control standard of care arm healed completely (P = 0.04).
2.2. Median time to complete healing was of 56 days in the TWO2 therapy arm and 93 days in the control standard of care arm (P = 0.04).
2.3. No ulcer reoccurrence was experienced during the 24 months follow up period.
2.4. Kaplan Meier curve of Time to Complete Healing:
IMAGE NOT AVAIALBE
3. Does Topical Wound Oxygen (TWO2) Offer an Improved Outcome Over Conventional Compression Dressings (CCD) in the Management of Refractory Venous Ulcers (RVU)? 
The aim of this controlled parallel arm study was to measure the effect of TWO2 on wound healing using the primary end-point of the proportion of ulcers healed at 12 weeks. Secondary end-points were time to full healing, percentage of reduction in ulcer size, pain reduction, recurrence rates and Quality-Adjusted Time Spent Without Symptoms of disease and Toxicity of Treatment (Q-TWiST).
A total of 83 patients were enrolled in the study with 46 in the TWO2 therapy arm and 37 in the conventional compression dressings (CCD) arm.
The Key Results were:
3.1. At 12 weeks, 80% of TWO2 managed ulcers were completely healed compared to 35% of the CCD managed ulcers (p < 0.0001).
3.2. Median time to full healing was 45 days in the TWO2 arm and 182 days in CCD arm (p < 0.0001).
3.3. The pain score threshold in the TWO2 managed patient arm dropped dramatically from 8 to 3 within 13 days.
3.4. After 12-month follow-up, 5 (38%) of the 13 CCD arm healed ulcers showed signs of recurrence compared to none (O%) of the 37 TWO2 healed ulcers (p < 0.0001).
3.5. The Quality-Adjusted Time Spent Without Symptoms of disease and Toxicity of Treatment (Q-TWiST) was significantly improved in the TWO2 managed patient arm (p < 0.0001):
IMAGE NOT AVAILABLE
4. Randomized Controlled Trial to Evaluate Different Treatment Regimes with Topical Wound Oxygen (TWO2) on Chronic Wounds 
This randomized cross-over controlled study was conducted in an outpatient setting on patients with severe diabetic foot ulcers (DFU) and chronic venous ulcers (CVU). All patients received TWO2 therapy for a period of one month. Then the groups were then randomized to either continue with TWO2, or to receive just Advanced Moist Wound Therapy (AMWT), for an additional 2 months.
The primary endpoints were complete ulcer closure after 12 weeks and incidence of amputation.
The Key Results were:
4.1. 82% of the patients were referred to the study center for minor or major amputation. All of these patients improved under the therapy and no patient underwent an amputation.
4.2. 90% of the DFU patients who received TWO2 therapy for the full 3 months healed completely within the 12 weeks, compared to only 40% of the patients that only received TWO2 therapy for one month and then AMWT for 2 months.
4.3. 50% of the CVU patients who received TWO2 therapy for the full 3 months healed completely within the 12 weeks, compared with just 30% of the patients that only received TWO2 therapy for one month and then AMWT for 2 months.
4.4. 93% of patients used analgesics at baseline. At the end of 3 months of treatment this was reduced to just 16%.
4.5. 66% patients had clinical infection on entry into the study, but after just the initial 4 weeks of TWO2 therapy this reduced to just 4%.
4.6. Kaplan Meier curve of Time to Complete Healing:
IMAGE NOT AVAILABLE
c. Additional Ongoing Randomized Controlled Trial on TWO2 therapy
To further reinforce the already extensive clinical evidence detailed above as to the Complete Healing, Quality Of Life and Health Economic benefits of TWO2 therapy, AOTI is currently enrolling subjects into an additional 220 patient Multi-national, Multi-center, Prospective, Randomized, Double Blinded, Placebo-controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen Therapy (TWO2) in the Treatment of Chronic Diabetic Foot Ulcers (ClinicalTrials.gov Identifier: NCT02326337) 
This state-of-the-art study protocol has been developed in collaboration with the world’s leading diabetic foot ulcer experts and includes opinion leader research sites across the USA and Europe. The study’s inclusion criterion allows for severe non-healing diabetic foot ulcers up to Stage 2D University of Texas Classification of Diabetic Foot Ulcers, defined as “wounds penetrating to tendon or capsule with infection and ischemia”. It also includes a 2 week run-in period with best standard of care to flush out wounds that would heal with this alone and a 12 month follow up to assess recurrence.
The study Primary Outcome Measure is:
- Incidence of Complete Wound closure within 12 weeks
The study Secondary Outcome Measures are:
- Time to complete wound closure
- Change in wound size over time
- Incidence of wound recurrence
- Incidence of amputation
- Incidence of adverse device effects
- Wound Patient Specific Quality of Life Assessment
- Various Health Economic Analyses
d. Is the use of TWO2 therapy in patients with chronic non-healing pressure ulcers, venous ulcers and diabetic foot ulcers reasonable and necessary under Section 1862(a)(1)(A)?
In being consistent with previous decision memorandums that CMS has issued on other wound care products , the evidence presented needs to be adequate to conclude that Medicare beneficiaries who have chronic non-healing diabetic, pressure, and/or venous wounds that receive TWO2 therapy would experience clinically significant health outcomes as indicated by at least one of the following:
- complete wound healing, or
- ability to return to previous function and resumption of normal activities?
AOTI believes that the evidence detailed in sections above demonstrates that Medicare beneficiaries who receive TWO2 therapy would experience clinically significant health outcomes indicated by both of these categories, in that TWO2 therapy has been shown in multiple controlled clinical trials and case series to heal Diabetic and Venous ulcers completely, at a statistically far higher rate than standard wound care alone. Also, by achieving this degree of complete wound healing with TWO2 therapy being applied by the patient at home, they are also more able to resume normal activities quicker for an improved quality of life (QOL).
Additionally, both the demographics of the patients enrolled in these studies, and the fact that TWO2 therapy has been reimbursed via our awarded Federal Supply Schedule contract for over five years (Contract No.:V797P-4209b)  and has been used extensively within the Veterans Administration , where we have successfully treated in excess of 10,000 patients with the majority of them being at home, we believe demonstrates that these wound healing and QOL outcomes are fully generalizable to the Medicare population.
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