Treatment of Mild, Moderate, and Severe Onychomycosis Using 870- and 930-nm Light Exposure

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1 ORIGINAL ARTICLES Treatment of Mild, Moderate, and Severe Onychomycosis Using 870- and 930-nm Light Exposure Adam S. Landsman, DPM, PhD* Alan H. Robbins, MD Paula F. Angelini, DPM Catherine C. Wu, DPM Jeremy Cook, DPM* Eric S. Bornstein, DMD Background: The Noveon is a unique dual-wavelength near-infrared diode laser used to treat onychomycosis. The device operates at physiologic temperatures that are thermally safe for human tissue. It uses only 870- and 930-nm near-infrared light, wavelengths that have unique photolethal effects on fungal pathogens. These wavelengths lack the teratogenic danger presented by ultraviolet light and the photoablation toxic plume associated with pulsed Nd:YAG lasers. Methods: In this randomized controlled study, treatments followed a predefined protocol and laser parameters and occurred on days 1, 14, 42, and 120. Toes were cultured and evaluated, and measurements were taken from standardized photographs obtained on days 1, 14, 42, 120, and 180. Results: We treated mycologically confirmed onychomycosis in 26 eligible toes (ten mild, seven moderate, and nine severe). All of the patients were followed-up for 180 days. An independent expert panel, blinded regarding treatment versus control, found that at 180 days, 85% of the treated toenails were improved by clear nail linear extent (P =.0015). Of the 26 toes, 65% showed at least 3 mm and 26% showed at least 4 mm of clear nail growth. Of the 16 toes with moderate to severe involvement, ten (63%) improved, as shown by clear nail growth of at least 3 mm (P =.0073). Simultaneous negative culture and periodic acid Schiff was noted in 30% at 180 days. [Q2] Conclusions: These results indicate a role for this laser in the treatment of onychomycosis, regardless of degree of severity. Ease of delivery and the lack of a need to monitor blood chemistry are attractive attributes. (J Am Podiatr Med Assoc 100(3): xxx-xxx, 2010) This article details a scientifically designed, randomized, single-blinded, controlled human study of the Noveon (Nomir Medical Technologies, Waltham, Massachusetts), hereafter referred to as the device. The device is a unique laser that has been specifically designed to treat the fungal pathogens associated with onychomycosis. The device uses only 870- and 930-nm light, two near-infrared wavelengths that have been shown to photoinactivate fungi and other *Division of Podiatric Surgery, Beth Israel Deaconess Medical Center, Boston, MA. Nomir Medical Technologies Inc, Waltham, MA. Southboro Medical Group, Southboro, MA. Private practice, Revere, MA. Corresponding author: Alan H. Robbins, MD, Nomir Medical Technologies Inc, 307 Waverley Oaks Rd, Ste 109, Waltham, MA ( cfolster@nomirmedical.com) [Q1] microbial pathogens. 1 This clinical trial was conducted to document the ability of the device to successfully treat toenail onychomycosis without thermal harm to the adjacent and healthy tissues. The protocol for the study under which these patients were treated was approved by the independent New England Institutional Review Board (Wellesley, Massachusetts) and the Beth Israel Deaconess Medical Center institutional review board. Advance discussion of the protocol with the Food and Drug Administration was conducted for the purpose of using certain data from the study for Food and Drug Administration 510(k) clearance to treat onychomycosis. In that regard, the study had two primary goals: demonstration of at least 3 mm of clear nail growth and attainment of negative mycologic response of at least 33.3%. The study was performed at four clinical sites. Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

2 The idea for this device was stimulated by the discovery by Neuman et al 1 that the use of 870- and 930- nm light would kill the microbial specimens they were observing using confocal microscopy (a technology by which individual living cells can be studied while held in multiple narrow beams of laser light). The design of the device takes advantage of the unique photolethal characteristics in each of the wavelengths described by Neuman et al and is further enhanced by the fact that killing of the pathogens is effected at dramatically lower energies than used in ablative or thermally lethal dosimetries with traditional medical laser systems (1.7 versus 1,000 2,000 W/cm). 2-5 Because of the low energies used and the consequently lower temperatures generated, the device is believed to pose no harm to tissues being exposed. Important also is that the wavelengths used are far from the ultraviolet range and, therefore, pose no potential for mutagenic effect. 6 An additional advantage is that unlike with photodynamic therapy, no photosensitizing agent is required when using the device. Photodynamic therapy has been cited by some researchers as a possible alternative to medication in the treatment of onychomycosis. However, getting a photosensitizing agent through the nail to the nail matrix poses a clinical challenge. 7-9 Before pursuing the present study, we performed a series of in vitro and in vivo studies (animal and human) using the 870- and 930-nm wavelengths and documented the feasibility of their clinical use in the treatment of infection. 4 Cadaver nail penetration studies demonstrated ample energy delivery through mycotic human nails to the nail bed to effect fungal decontamination. Another study confirmed the previously postulated mechanism of action: interaction of the wavelengths with plasma and mitochondrial membranes and the generation of endogenous radical oxygen species causing photodamage and photoinactivation of fungi and bacteria. 4, 10 These studies demonstrated the selectiveness of these wavelengths to negatively affect only fungi and bacteria, not mammalian cells. Sensitivity studies showed that along with Staphylococcus aureus and Escherichia coli, Candida albicans and Trichophyton rubrum were among the most sensitive to exposure to these wavelengths. 2, 4 Methods The Device In the protocol approval process for this study, both institutional review board panels determined that the device met the Food and Drug Administration standard for being in the nonsignificant risk category. 11 Previously 510(k) cleared for noncontact and contact use by the Food and Drug Administration in podiatric medicine, dermatology, plastic surgery, and otolaryngology, [Q3] the device has not yet been specifically cleared for the treatment of onychomycosis. The device operates in continuous-wave format and at only two wavelengths, 870 ± 5 nm and 930 ± 5 nm, both of which are in the near-infrared spectrum. It is designed to use both of these wavelengths at a maximum power density of 1.7 W/cm 2. The two wavelengths may be used simultaneously, and either wavelength can be used alone. To ensure consistency of dose, a flat-top microlens was used to effect a uniform power density in the treated area. In addition, the device has user-programmable settings for storing frequently used parameters. Patients All of the patients were 18 to 70 years of age, provided signed informed consent, and had at least one great toe with distal/lateral or superficial white onychomycosis that did not involve the lunula or extend to the eponychium. If the second great toe had onychomycosis that fulfilled the eligibility requirements, it was included in the basic study. If the second great toe had onychomycosis that did not meet the eligibility requirements because of type or distribution, including lunular involvement, it could be treated as a companion toe but was not included in the primary study. All of the patients had to have laboratory confirmation of onychomycosis by either positive culture using a selective dermatophyte test medium (ACU- DTM; Acuderm Inc, Ft Lauderdale, Florida) or positive periodic acid Schiff staining from a toenail sample. Skin color had to be Fitzpatrick grade I to IV (excludes grades V and VI, the two darkest shades). Diabetic patients without evidence of neuropathy or peripheral vascular disease were included. Patients with psoriasis, lichen planus, or a history of trauma to the toe were excluded. Immunocompromised individuals, including those with human immunodeficiency virus, were excluded. Patients who had received prescription antifungal medications, either topically or systemically, within 6 months were excluded. The independent monitoring contract research organization (Medical Device Consultants Inc, Attleboro, Massachusetts) created the randomization schedule and assigned patients to the treatment or control group in advance of treatment. Only after eligibility was established was patient assignment made. Patients were blinded as to whether they were to receive real treatment or a sham. The investigators 2 May/June 2010 Vol 100 No 3 Journal of the American Podiatric Medical Association

3 were not blinded to allow them to operate the device or oversee its operation and document that the device settings being used were correct. Treatment Protocol and Evaluation A summary of the various protocol elements is given in Table 1. Each treated toe received four treatments. After baseline evaluation, the first treatment was given on day 1. The remaining treatments were given on days 14, 42, and 120. Purely follow-up (nontreatment) visits were conducted at approximately 60 and 180 days. [Q4] At all of the visits, nail samples were collected for culture and periodic acid Schiff staining. In addition, clinical observations were made by the investigator to assess improvement. To ensure accuracy of dosage, the laser was calibrated before the first treatment of the day and between each patient. The beam diameter used ranged from 1.5 to 1.9 cm, at the discretion of the investigator, depending on the size of the toe and the diameter required to effect complete coverage. Each treatment consisted of two exposures directed at the toenail: a 4-min exposure applying both wavelengths (870 and 930 nm) simultaneously and a second exposure with 930 nm alone for 2 min. The specific parameters for each of the two exposures in each treatment were identical for all of the patients and treated toes (Table 2). [Q5] A noncontact infrared thermometer was used to measure temperatures at the treatment site. A baseline temperature reading of the treatment area was obtained, after which temperatures were taken at 30- to 60-second intervals and recorded. If a surface temperature reading greater than 102 F was measured, the laser treatment was to be interrupted and resumed only when the reading had fallen below 98 F. If interruption of the treatment was required because of patient discomfort, the treatment was resumed when the patient was again comfortable as long as the temperature was less than 102 F. Starting after completion of the second of the four treatments, all of the patients were required to use a nonprescription topical agent: topical terbinafine, 1%, cream applied between the toes only to control or prevent tinea pedis. Use of that agent was in accordance with the current listed product information 12 and is neither indicated or cleared by the Food and Drug Administration as a treatment for onychomycosis. Other nonpharmaceutical adjunctive actions that would otherwise be standard care, such as nail debridement and nail trimming, were allowed at the investigator s discretion. Control subjects were handled identically in all respects as those who were treated except that when a sham treatment was being given, there was no energy output (ie, the laser power was set to zero). All of the included toes were visually evaluated by the investigators at predetermined intervals for subjective signs of improvement or deterioration using the following scale: completely cleared, markedly improved, slightly to moderately improved, unchanged, and worse. [Q6] Standardized photographs of the toes were taken on the first treatment day (baseline) and on days 14, 42, 120, and 180. [Q7] An independent expert panel used the baseline photographs to classify each toe by the degree of nail plate involvement at the outset as mild (<1/3 involvement), moderate (1/3 2/3 involvement), or severe (>2/3 involvement). 13 Follow-up photographs on days 120 and 180 were used by the panel to subjectively grade clinical improvement with the scale for clinical assessment mentioned in the previous paragraph. In addition, the panel outlined the clear nail area on the photographs of each toe. Using these outlines, computer software (Mirror PhotoFile; Canfield Imaging Systems, Fairfield, New Jersey) was used to delineate the degree of improvement, or lack thereof, during Table 1. Study Procedures Baseline Day 1 Day 7 Day 14 ± 2 Day 60 ± 5 Day 120 ± 10 Day 180 ± 10 Consent form X Inclusion/exclusion X Randomization X Study treatment X X X X Visual assessment X X X X Culture and PAS staining X X X X X X X Photographs taken X X X X Clear growth measurement X X X X X X Adverse event recording X X X X X X Abbreviation: PAS, periodic acid Schiff. Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

4 Table 2. Noveon Laser Factors for the 4- and 2-min Exposures Output Power Beam Spot Area of Spot Time Total Energy Energy Density Power Density (W) (cm) (cm 2 ) (sec) (J) (J/cm 2 ) (W/cm 2 ) 4-min exposure 870 nm nm Combined min exposure 930 nm the study in the target toenails (treatment and control) by measurement of maximum linear clear nail growth. All adverse events, whether anticipated or unanticipated, were noted, classified, and documented in accordance with the following definition, as stated in the study protocol: A serious adverse event is one that results in death, is life-threatening, or results in hospitalization (or prolongs a hospitalization), persistent or significant disability or incapacity, congenital anomaly/birth defect, or medical/surgical intervention to prevent one or more of the aforementioned events. All other adverse events were classified as non-serious adverse events. In addition, all failures and malfunctions of the Noveon device were documented. The independent contract research organization monitored the study and completed statistical calculations on the results. The analysis of data is primarily based on the number of individual toes treated because each treatment is localized, and each treatment is effectively topical and without any known systemic effect. Results General Comments Of 36 individuals enrolled (26 men and 10 women), 34 were eligible for inclusion in the primary study (25 treated patients and 9 controls) (Table 3). From these 34 patients, there were 37 toes eligible for inclusion in the primary study (Table 4). Three of the toes treated were from diabetic patients (one had type 1 and two had type 2). Of the 37 toes in the eligible group, only one was considered to be purely superficial. The remaining 36 toes were considered to be distal/lateral, eight of which were considered to have superficial elements. None of the toes were considered to represent total dystrophic disease, proximal subungual disease, or endonyx subungual disease, all of which were excluded per protocol. Also excluded from eligibility in the Table 3. Patient Disposition by Study Group Treatment Control Group Group Total (n = 26) (n = 10) (N = 36) Enrolled in the study (No.) a Intention-to-treat population (No.) b Per-protocol (eligible) population (No.) c a The enrolled population includes all of the patients who signed consent forms and were randomized. b The intention-to-treat population includes all of the patients who signed consent forms, were randomized, and completed visit 1. c The per-protocol population includes all of the patients who signed consent forms, were randomized, completed visit 1, and met the inclusion and exclusion criteria. Table 4. Summary of Toes by Study Group Treatment Control Group Group Total (n = 44) (n = 15) (N = 59) No. of intention-to-treat toes No. of all treatable toes a No. of toes eligible to be treated a Includes companion toes, which, per protocol, could be treated but were ineligible to be included in the primary test group because disease was too extensive or involved the lunula. basic study per protocol were toes with lunular involvement. However, the study protocol was designed such that the second large toe could be treated and included in the study results regardless of degree of severity. Based on that secondary grouping, an additional 16 (14 treated and two control) toes were included in the overall study as companion toes. Of the 14 additional treated toes, 13 had lunular involvement. The results from the primary treatment group of 37 toes based on the protocol are presented herein as 4 May/June 2010 Vol 100 No 3 Journal of the American Podiatric Medical Association

5 the eligible group. The results from those toes and the companion toes are included herein as the alltreated group (53 toes [40 treated and 13 control]). Mycologic Assessment The entry criteria required confirmation of onychomycosis by a positive culture, positive periodic acid Schiff staining, or both. Nevertheless, both tests were performed on all of the toes. In the eligible group, the diagnosis of onychomycosis was confirmed by both fungal culture and periodic acid Schiff staining in 17 toes, by culture alone in three, and by periodic acid Schiff staining alone in 17. In the all-treated group, the diagnosis of onychomycosis was confirmed by both fungal culture and periodic acid Schiff staining in 26 toes, by culture alone in four, and by periodic acid Schiff staining alone in 23. Only five (three treated and two control) toes were positive for C albicans; all others were positive for a dermatophyte. The three treated toes that were initially positive for C albicans became negative within 14 days (two treatments). In the eligible group, 12 of the treated toes were culture positive (two for C albicans and ten for a dermatophyte). Separate tracking of negative culture and periodic acid Schiff staining in eligible treated toes that were initially positive at the outset showed that there was a steady rise in negative culture and negative periodic acid Schiff staining. Negative culture was noted in 42% of toes after only one treatment and attained a peak of 75% on day 60, whereas a peak of 64% negative periodic acid Schiff staining was attained at day 120 (Fig. 1). The 60-day lag in the periodic acid Schiff negative result presumably reflected the fact that due to this biopsy-based sampling, sufficient nail growth is necessary for a true-negative result because a false-positive result is produced when pathogens, although dead, are still recognizable in the nail tissue. It is also possible that this lag reflected reinfection from shoes worn by the subject or from tinea pedis. The presence of tinea pedis was not an exclusion factor but was, in fact, presumed to be present in all cases. Nail dystrophy could also account for the lag, but assessment of such was not part of the study. Also of note is the fact that at day 180, 39% of the eligible group treated toes attained both stated goals of the study by simultaneously showing negative culture and at least 3 mm of clear nail growth (Fig. 2). Subjective Assessments by the Investigators and the Independent Panel Baseline Severity. As seen in Table 5, which includes only the eligible toes, the investigators perceived the degree of severity at the outset to be more serious than the panel did. This was also true when all-treated toes were assessed (includes all companion toes that exceeded eligibility for the primary study but were treated according to the protocol) (Table 6). The investigators perceived the degree of involvement at the outset to be more serious than the independent panel did, and that difference is significant (P =.0440). Overall Improvement at 180 Days. In the subjective visual assessment of improvement in eligible treated toes, the investigators judged 24 of 26 toes (92%) to have improved to some degree and none to Toes with Negative PAS Staining (%) Baseline Day 1 Visit 1 R x 1 Day 14 Visit 2 R x 2 Topical Terbinafine Initiated Day 42 Visit 3 R x 3 Day 60 Visit 4 R x 4 Day120 Visit 5 Day180 Visit 6 Figure 1. Tracking of negative periodic acid Schiff (PAS) staining in eligible toes with positive PAS staining at baseline. R x indicates study treatment. Toes (No.) Treated Control 10/26 39% Baseline Day 180 Visit 6 P = /11 9% Figure 2. Eligible toes with negative culture and at least 3 mm of clear nail growth at day 180. Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

6 Table 5. Severity of Disease at Baseline: Eligible Toes Eligible Toes (%) Treatment Control Total Group Group (N = 37) (n = 26) (n = 11) Rating by investigators Mild Moderate Severe Rating by independent panel Mild Moderate Severe Table 6. Severity of Disease at Baseline: All-Treated Toes All-Treated Toes (%) Treatment Control Total Group Group (N = 53) (n = 40) (n = 13) Rating by investigators [Q12] Mild Moderate Severe Rating by independent panel Mild Moderate Severe be worse or unchanged, and the independent panel judged 20 of 26 toes (77%) to have improved and 23% to be unchanged or worse (Table 7). The investigators and the independent panel noted improvement in most of the treated toes. However, the degree of difference between the two groups (investigators versus panel) is significant (P =.0092). The fact that the unblinded study investigators perceived that their subjects had worse disease at the outset and a better overall response at day 180 compared with the blinded independent panel is not surprising. In addition to the inherent bias of enthusiastic investigators, note that the investigators based Table 7. Clinical Assessment by Study Group at 180 Days: Eligible Toes Eligible Toes (No. [%]) Treatment Control Total Group Group (N = 37) (n = 26) (n = 11) Comparison with baseline by investigator Unchanged or worse 0 2 (18.2) 2 (5.4) Slightly to moderately 19 (73.1) 7 (63.6) 26 (70.3) improved Markedly improved 5 (19.2) 2 (18.2) 7 (18.9) Completely cleared Missing 2 (7.7) 0 2 (5.4) Comparison with baseline by independent panel Unchanged or worse 6 (23.0) 6 (54.5) 12 (32.4) Slightly to moderately 18 (69.2) 3 (27.3) 21 (56.8) improved Markedly improved 1 (3.8) 2 (18.2) 3 (8.1) Completely cleared 1 (3.8) 0 1 (2.7) Missing their assessments on actual visual assessments and that the independent panel made assessments only from high-quality photographs without patient contact or knowledge of treatment versus control status. To facilitate objectivity in the analysis of these data, therefore, the following sections of this article are based entirely on input from the independent panel, unless otherwise specified. A similar percentage of treated (17.5%) and control (15.4%) toes were judged by the independent panel to have worsened at 180 days. The lack of disparity in these groups suggests that the worsening was not attributable to the treatment but was merely indicative of the natural progression of the disease in cases unresponsive to the treatment. Representative treated cases with observed improvement are shown in Figures 3 through 7. Assessment of Clear Nail Linear Growth As noted earlier, we chose to use only the outlines of involved nails on the interval photographs created by the independent panel for the calculations given in Tables 8 to 10. Improvement in clear linear nail growth in the eligible group as measured at day 180 for treated versus control patients is summarized in Table 8. Using this more objectively obtained assessment, 85% of the treatment group showed measurable clear nail growth, and 65% showed at least 3 mm of clear nail growth. The mean clear growth measurement noted in the treatment group is significantly greater than that in the control group (P =.0015). The calculated rate of nail growth in the treatment group is also significantly greater than that observed in the control group (P =.0167). However, the mean observed rate of clear nail growth in treated toes in the eligible group was mm per day, clearly lower than the 6 May/June 2010 Vol 100 No 3 Journal of the American Podiatric Medical Association

7 A B Figure 3. Representative treated case with mild distal/lateral disease at baseline (A) and after 180 days (B). A B Figure 4. Representative treated case with moderate superficial disease at baseline (A) and after 180 days (B). mean in normal great toes reported by Edwards and Schott in their classic study. 18 [Q8] The results obtained when eligible treated toes are sorted by degree of severity at the outset of the study are given in Table 9. Treatment outcome is demonstrated by the percentage of toes that attained at least 3 mm of clear linear nail growth. The results in treated toes are significantly better than those in toes in the control group (P =.0112). In addition, the percentage of successful outcomes in treated toes with severe disease was essentially the same as that in toes with mild disease. These results are further underscored when one examines the all-treated group because that group contains a disproportionate number of toes with more advanced disease. As seen in Table 10, 48% (19 Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

8 A B Figure 5. Representative treated case with severe disease in a companion toe involving the entire nail at baseline (A) and with complete healing at 180 days (B). A B Figure 6. Representative treated case with mild disease at baseline (A) and with, at most, minimal residual disease after 180 days (B). s s e r p in of 40) of the all-treated group showed at least 3 mm of clear linear nail growth versus 8% in the control group. These results are significant (P =.0073). Twelve of the 19 toes (63%) that showed clear nail growth started with moderate or severe disease, and seven of the 19 (37%) showed at least 4 mm of clear nail improvement after treatment. Indeed, the percentage with at least 3 mm of response in those with 8 severe disease (53%) was comparable with that of those with mild disease (58%). By comparison, of the 13 toes in the control group, four were mild cases and nine were moderate to severe cases. The one control case that demonstrated at least 3 mm of improvement was categorized as mild, and none from the moderate and severe categories attained this improvement level. An additional observation was that of the 13 May/June 2010 Vol 100 No 3 Journal of the American Podiatric Medical Association

9 A B Figure 7. Representative treated case of severe disease in a companion toe at baseline (A) and showing marked improvement by day 120 (B). toes with lunular involvement, five (38%) showed at least 3 mm of clear nail growth. The number of treated toes that showed improved linear clearing as judged by the independent panel after 120 days was compared with the findings after 180 days (Fig. 8). Although the difference did not attain statistical significance, there is an obvious trend toward increasing success at the 180-day interval. Table 8. Clear Linear Nail Growth at 180 Days: Eligible Toes (as Determined by the Independent Panel) Eligible Toes (No. [%]) Treatment Group (n = 26) Control Group (n = 11) Total (N = 37) P Value a Clear growth (mm) b <1 4 (15.4) 6 (54.5) 10 (27.0) (19.2) 4 (36.4) 9 (24.3) 3 17 (65.4) 1 (9.1) 18 (48.6) Mean clear nail growth rate (mm/toe/d) c a Values for clear growth and growth rate were obtained with the 2-sample Wilcoxon-Mann-Whitney test; the P value for clear growth by category was obtained with the exact Kruskal-Wallis test. b Calculated as the difference between clear linear distance at baseline and 180 days. c Growth rate = Sum of Clear Nail Growth/No. of Toes/180 Days. a The P value was obtained with the exact Kruskal-Wallis test Table 9. Toes Attaining at Least 3 mm of Clear Linear Nail Growth at 180 Days in the Eligible Group (as Determined by the Independent Panel) Eligible Toes (No. [%]) Treatment Group Control Group Total P Value a Baseline severity.0112 Mild 7/10 (70) 1/4 (25) 8/14 (57) Moderate 3/7 (43) 0/6 3/13 (23) Severe 7/9 (78) 0/1 7/10 (49) All 17/26 (65) 1/11 (9) 18/37 (49) a The P value was obtained with the exact Kruskal-Wallis test. Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

10 Table 10. Toes Attaining at Least 3 mm of Clear Linear Nail Growth at 180 Days in the All-Treated Toes Group (as Determined by the Independent Panel) Eligible Toes (No. [%]) Treatment Group Control Group Total P Value a Baseline severity.0073 Mild 7/12 (58) 1/4 (25) 8/16 (50) Moderate 4/10 (40) 0/6 4/16 (25) Severe 8/15 (53) 0/3 8/18 (44) All 19/40 (65) 1/13 (8) 20/53 (38) a The P value was obtained with the exact Kruskal-Wallis test. [Q13] Safety Discussion Cumulatively, 156 treatments were given during the study. Because each treatment consisted of two exposures (4 min at 870 and 930 nm combined and 2 min at 930 nm alone), during the study there were 312 separate exposures. There were no serious adverse events, as previously defined (see the Treatment Protocol and Evaluation subsection). The only procedure-related events noted were nonserious and consisted of the sensation of heat or tingling noted during approximately half of the 312 exposures. This included one of the three toes treated in diabetic patients. In no case was it necessary to terminate a treatment. The temperature readings from the treated site never exceeded 94 F in any treatment in the series. One treated toe developed a subungual hematoma in the treated area that, according to the patient, was caused by trauma (ie, stubbed toe) that occurred several weeks after the third treatment. It was considered to be unrelated to the procedure. There were no device malfunctions or failures. Toes (%) Figure 8. Eligible toes with at least 3 mm of clear nail growth and negative culture. It has been estimated that 6% to 13% of the North American population has onychomycosis, with most cases being caused by T rubrum. 13 More than just a cosmetic issue, it can cause considerable pain and can lead to infections of the toes that may ultimately result in amputation. In this regard, patients with diabetes and neuropathy are at particular risk. Thus, although the cosmetic and psychological need to effectively treat the disease is important, prevention of the complications is even more important. A plethora of treatment options are in use today, frequently being used in combination. 14, 15 Despite the many options, there continues to be ongoing debate about the ability to effect cure and even what cure means. Indeed, acknowledged experts have indicated that perhaps the more realistic goal should be to optimize management of the disease in light of its great propensity to recur. 16 Whatever the goal, treatments for onychomycosis continue to focus on variable combinations of debridement, topical antifungals, oral antifungals, and proper foot hygiene. Although debridement reduces the immediate risk associated with nail bed perforation and onychocryptosis, it is certainly not a cure and will require subsequent continual treatments, often for life. Total removal of the nails is also sometimes considered, but this treatment eliminates the protective covering of the toes and has a poor cosmetic result. Topical antifungals range from home remedies, such as strong tea or bleach; to homeopathic treatments, such as tea tree oil; to the Food and Drug Administration cleared synthetic antifungal ciclopirox used in an 8% nail lacquer (Penlac; Dermik Laboratories, Berwyn, Pennsylvania). Oral options include terbinafine, griseofulvin, and the azoles (ketoconazole, itraconazole, and fluconazole). These products have been shown to be effective at eliminating onychomycosis, with some studies reporting up to 59% mycologic cure (simultaneous Treated (n = 26) Control (n = 11) Baseline 120 Days 180 Days 10 May/June 2010 Vol 100 No 3 Journal of the American Podiatric Medical Association

11 negative culture and negative periodic acid Schiff staining) and at least 5 mm of new clear nail growth occurring after follow-up of 48 weeks (336 days). 17 This rate occurred only after daily oral/systemic administration of these drugs for 3 months or more. Concern about liver toxicity and drug interactions has limited access to these medications to individuals with normal liver function who are taking relatively small amounts of other hepatically metabolized medications and who are willing to undergo follow-up laboratory testing to ensure that no damage to the liver is taking place. Therefore, it is not surprising that many patients, and their physicians as well, opt to avoid the potential risks of oral treatments and elect relatively ineffective topicals or simply resign themselves to a lifetime of debridement. The need for better or safer treatments for onychomycosis has led to the development of the unique laser technology used in this study. The results of this study confirm in human patients our earlier laboratory data demonstrating the feasibility of using 870- and 930-nm light to kill the fungus that causes onychomycosis on a purely photonic basis, at very low energy, and at physiologic temperatures. 2-4 The ability of the device to directly affect the fungi causing onychomycosis in the patients in this trial was demonstrated by the fact that after only one treatment, negative culture was observed in 42% of the eligible toes that had positive cultures at the outset and that by day 60, after three 6-minute treatments, 75% showed negative culture. These observations are clear indicators of therapeutic success from which future regimens can be modified to further optimize the laser s mycologic impact. Similar to most, if not all, other treatment options, clinical improvement depends largely on the speed of nail growth. This study indicates that treatment with the device is not likely to be an exception. However, it is apparent that the measurable response in treated nails was far greater than that in controls. Although the mechanism for this may simply be elimination of the infecting agent, allowing more normal growth to proceed, the observation is consistent with a recent study in which it was noted that an apparent angiogenic switch is activated in human skin by acute IR irradiation. 19 [Q9] The possibility of actual direct stimulation of nail growth by device exposure is an aspect that should be further assessed. The results of this study portend clinical usefulness for the device from a variety of perspectives. This study documented a measurable effect on mycologic cure, acutely and during 6-month follow-up. The study documented clear nail growth in treated toes that is significantly better than that observed in the control group. Nail growth does not seem to have been impeded by treatment exposure and may have been facilitated. The lack of medication toxicity monitoring is a definite advantage. The device seems to be comparably effective regardless of disease severity, and it was demonstrated to be safe, reliable, and devoid of systemic risk. Conclusions Use of the device was demonstrated to have a positive effect on great toenails with onychomycosis, regardless of the severity of the disease. Positive impact was demonstrated by clinical appearance, measurement of clear nail area, measurement of clear nail linear growth, and attainment of negative fungal culture. The device has been demonstrated to be reliable and safe, reflecting, at least in part, the fact that the mechanism of action for fungal inactivation with the device is purely photobiological. The device does not depend on ablation, high heat, chemical potentiators, or any wavelength in the ultraviolet range, which would be inherently more dangerous or mutagenic At least one of these disadvantages is characteristic of each of the other systems currently in use or under investigation. 2 The data contained in this assessment indicate that this device has great potential to be a useful new component in the treatment of patients with the difficult clinical challenge presented by onychomycosis, regardless of whether the involvement is mild, moderate, or severe. Financial Disclosure: This study was exclusively funded by Nomir Medical Technologies, Inc. The protocol was created by Nomir Medical Technologies, Inc, with minor input from the lead author. The conduct of the study and collection of data was entirely up to the investigators. Analysis and interpretation of the data had input from all investigators and authors. Dr. Robbins of Nomir Medical Technologies was actively involved in the preparation, review, and approval of the manuscript. All authors reviewed and approved the final manuscript. Conflict of Interest: Drs. Robbins and Bornstein are employees of Nomir Medical Technologies, Inc, and each has a financial interest in the company. References 1. NEUMAN KC, CHADD EH, LIOU GF, ET AL: Characterization of photodamage to Escherichia coli in optical traps. Biophys J 77: 2856, BORNSTEIN E: A review of current research in light-based technologies for treatment of podiatric infectious disease states. JAPMA 99: 348, Journal of the American Podiatric Medical Association Vol 100 No 3 May/June

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