LOW LEVEL LASER THERAPY
Many people are uncomfortable with thick, brittle, yellow nails caused by fungus. There are many topical and oral medications, but they all have limitations. Because of this killing nail fungus is a hot topic right now with podiatrists and, because of this, they are waking up to the value of laser therapy.
In this study, (Photochem and Photobiol 2009 Nov-Dec;85 (6):1364-74), infrared laser was used to treat toenail fungus with a power density of 5.66 W/cm2. The goal of the study was to find out what dose would be most effective at killing fungus while not damaging tissue.
They tested a number of organisms, including the fungus Trichophyton rubrum (Tinea unguium is the organism responsible for nail fungus). They noted that the laser treatment caused a decrease in membrane function and an increase in oxygen generation (ROS), a sign of cellular stress. The authors postulate that these wavelengths caused damage to the cell, harming its ability to function properly. No observable damage to the nail matrix or mucous membranes was observed, yet photodamage to the pathogens was achieved. What this study points out is that to kill the fungus, one needs a laser that is hot enough to damage the fungal cells,
but low enough to not burn the tissue.
Laser Treatment for Toenail Fungus
David M. Harrisa,b, Brian A. McDowellc, John Strisowerb
a Univ. of Washington, Seattle WA, USA 98195; bPathoLase, Inc. 275 Airpark Blvd., Chico, CA 95973; cNorthern California Orthopedic Centers, 6403 Coyle Avenue, Carmichael, CA, USA 95608
Photonic Therapeutics and Diagnostics V, edited by Nikiforos Kollias,Bernard Choi, Haishan Zeng, Reza S. Malek, Brian Jet-Fei Wong, Justus F. R. Ilgner, Kenton W. Gregory, Guillermo J. Tearney, Laura Marcu, Henry Hirschberg, Steen J. Madsen, Proc. of SPIE Vol. 7161, 71610M Â· Â© 2009 SPIE Â· CCC code: 1605-7422/09/$18 Â· doi: 10.1117/12.810193
An infrared pulsed laser was used to irradiate toenails with visible signs of bacterial/fungal infections. Seventeen subjects with both great toes involved were recruited in a podiatric private practice. Toes were randomized to receive either a single treatment or no treatment. The treatment was tolerated by all subjects without anesthesia and there were no occurrences of serious adverse effects. Eleven out of 14 (79%) treated toes improved. Improvement ranged from 2.1 to 6.1 mm over 90 days following a single treatment. There was a highly significant difference (p<0.001) between treated and untreated toes for nail bed clearing.
Keywords: Laser, onychomycosis, toenail fungus.
Onychomycosis is a chronic fungal nail infection that affects 7-10% of the U.S. population and can have serious consequences to the elderly, diabetics, and immunocompromised individuals. Dermatophytes (including the genera Trichophyton, Epidermophyton and Microsporum) are the most common pathogens of onychomycosis,1-3 with T. rubrum accounting for 80% of the infections.4
The efficacy of current treatment options, including topical, oral, mechanical and chemical therapies or a combination of these modalities is low.5,6 Topical drug treatment for onychomycosis is not usually successful because they are unable to penetrate the nail plate7,8 and rapid recurrence can occur after discontinuing use.9,10 Oral antifungal agents are more effective although more toxic with a significant risk of liver toxicity, prolonged loss of taste, and life-threatening drug interactions.11 Fungal resistance can occur when the oral antifungal agents are used on a long-term basis. Topically applied antifungal drugs may work somewhat better adjunctive to surgical removal or chemical dissolution of the nail plate.12 Yet, this often ineffective and traumatic procedure leaves the subject without a nail for months at risk for reinfection.
Given the limitations of current treatment options, there is a great need for a simple, nontoxic and effective alternative treatment.13 In an initial clinical trial an infrared pulsed laser was used to irradiate toenails with visible signs of bacterial/fungal infections. The following is a report of the clinical data from that trial designed to evaluate the safety and efficacy of a prototype antifungal laser, the PinPointe™ FootLaserTM by PathoLase, Inc. (Chico, CA).
2. EXPERIMENT DESIGN
Seventeen volunteer subjects with both great toes involved were recruited in a podiatric private practice. All subjects signed informed consent forms. Subjects were of either sex, 18 years or older, with right and left great toe involvement (e.g., current bacterial/fungal infection classified by the investigator as subungual onychomycosis). Subjects were also required to provide Informed Consent and be available for study follow-up visits and evaluations. Subjects were excluded from study if they were pregnant, had been treated with oral Lamisil (terbinafine hydrochloride) within one year prior to study treatment, had been treated with or taken Penlac (ciclopirox), Sporanox (Itraconazole) or over-the-counter (OTC) remedies for toenail infection within 4 weeks prior to study treatment, were determined by the investigator to be incapable of study compliance, or at the professional discretion of the investigator.
Right or left great toes were randomized to receive either a single treatment or no treatment. Nails were not debrided. A notch was placed near the proximal extent of each nail with a triangular file and a calibrated 1-cm scale was placed on the toe. Nails were photographed with a high resolution digital camera before treatment, immediately posttreatment and at 1 week and monthly up to three months when data were analyzed. At that time the untreated toes were treated (crossover design) and subjects were followed an additional three months out to 6 months post-treatment. Nail plate growth and nail bed clearing at 3 months were measured from the photographs using Image J software by an evaluator who was blinded to the treatment condition.
Figure 1. Typical response to treatment. Left: Top treated, bottom untreated. Pretreatment on the left followed by images at 1, 2 and 3 months.
Below: distance of the lesion from the proximal fold (mm). Subject 006 absolute distance and #14 normalized distance. Blue treated, red untreated.
3.1 Demographics and Baseline Characteristics
Mean age of the study patients was 67.3 +/- 12 years (range 46 - 89 years; n=17); 65% (11/17) males and 35% (6/17) females. 94.1% (16/17) subjects were Caucasian and 5.9% (1/17) were Hispanic. The median duration of toenail infection among the study patients was > 10 years (range 2 - 50 years; n=17).
The treatment was tolerated by all subjects without anesthesia. However, during the course of the study, a total of 9 adverse events were reported by 5 patients, mostly mild to moderate discomfort during the procedure. There were no reports of nail plate or nail bed damage or discoloration, nor was there any post-operative discomfort related to
3.3 Individual data
The effect of treatment is illustrated by the individual examples in Figure 1. The treated toe of Subject 006 responded well to a single treatment. By 3 months post-treatment, there is 4 mm of clear nail growth. The right foot was untreated and the lesion did not "grow out." Note that the notch on the treated foot moves out at a faster (variable) rate than the lesion whereas, in the untreated foot the notch grows out but the lesion remains stationary. Notice also that the treated toe of subject 14 is onycholytic (nail plate is separated from the nail bed), but this has resolved following treatment.
3.4 Summary data
The analysis of the data at three months revealed that notch measurements increased in a similar fashion for both toes with no difference between treated and untreated toes (p=0.810). There was a highly significant difference (p<0.001) between treated and untreated toes for the lesion measurement. For treated toes, clear nail average values went from 4.0 mm at baseline to 7.7 mm at 90 days, while the untreated toes went from 5.3 at baseline to 5.6 mm at 90 days. Eleven out of 14 (79%) treated toes improved. Improvement ranged from 2.1 to 6.1 mm over 90 days following a single treatment For the 14 toes that responded to therapy the average improvement was 3.9 mm, or 1.3 mm per month.
3.5 Notch measurements and the rate of nail plate growth
Each nail had a unique growth rate that would vary from month to month. Also, left and right great toenails would often grow at different rates on the same person. Table 1 shows the summary statistics for notch and measurements for the 16 patients in the analysis and Figure 2 shows that overall there were no differences in nail plate growth rate. Table 2 summarizes the results of repeated measures analysis of variance. The primary factor of interest is the treatment by time
interaction which compares the changes over time between treated and untreated toes (essentially the slopes of the response curve). Notch measurements increased in a similar fashion with no difference between treated and untreated toes (p=0.330).
Figure 2. Growth of the nail plate as the distance in mm from the original notch location at monthly intervals. There is no difference between treated and untreated toes (p=0.330).
|TABLE 1 SUMMARY STATISTICS FOR NOTCH MEASUREMENTS. Values are distance of the notch from the proximal fold in mm’s.|
|The following results are for: VARIABLE = Notch|
|N of cases||15||14||15||15||14|
|N of cases||15||14||15||15||14|
3.5 Lesion measurements and the rate of nail bed clearing
There was a highly significant difference (p<0.001) between treated and untreated toes for the lesion measurement. For treated toes, lesion average values went from 4.0 at baseline to 7.3 mm at 90 days, while the untreated toes went from 5.3 at baseline to 5.6 mm at 90 days. Eleven out of 14 (79%) treated toes improved. Improvement ranged from 2.1 to 6.1 mm over 90 days following a single treatment. For the toes that responded to therapy the average improvement was 4.0 mm, or 1.3 mm per month.
|TABLE 2 SUMMARY STATISTICS FOR LESION MEASUREMENTS. Values are distance of the notch from the proximal fold in mm’s.|
|The following results are for:VARIABLE = Lesion|
|N of cases||15||14||15||15||14|
|N of cases||15||14||15||15||14|
Figure 3. Nail bed clearing plotted as the distance in mm from the original lesion location at monthly intervals. There is a significant difference between treated and untreated toes (p<0.001.)
Subjects were followed and photographed out to 6 months post-treatment. Figure 4 shows images for Subject 6 and 14 out to 6 months (Also shown in Figure 1).
In conclusion, there appeared to be no discrimination between treatment and no treatment for notch measurements, however, there were highly significant treatment differences for lesion measurements.
Figure 4. Patient 6 improved up to 3 months but after 3 months the lesion progresses proximal. Although still improved, the best result was at 3 months. At six months after a single treatment, the treated toe of Subject 14 continues to improve.
Comparison of nail plate (notch) growth rate and nail bed (lesion) clearing rates reveals that the nail plate grows about twice as fast as the lesion clears out of the nail bed (Figure 5). Time for complete clearing is dependant on the original amount of involvement. We predict that complete clearing of a totally involved great toe should take up to12-18 months and we continue to follow these patients.
We note that the notch grew out at the same rate on the treated as on the untreated toe. This means that there is neither an obvious biostimulatory effect of laser light on nail plate growth nor is there an inhibitory effect. There were no visible effects of treatment (discoloration, surface texture changes, etc.) seen in any of the photographs or reported by the investigator. In this sample of 17 patients treatment of the toenail with the FootLaser did not damage the nail plate, the underlying nail bed, the matrix, or the surrounding tissue. On the contrary, in a few of the subjects (for example Figure 1 and Figure 4, Subject 0014) an irregular contoured nail grew out looking smooth and natural.
Some subjects (18%) reported mild to moderate intraoperative discomfort although all subjects tolerated the entire procedure. No toxicity, side-effects or drug interactions occurred. Results reported here were from a single treatment so, except for sitting still during the procedure, additional patient compliance was unnecessary.
In this study, we selected difficult to treat infections, such as patients with fungal spikes,14,15 onycholytic and/or hypertrophic nails. Even though these patients are typically excluded in drug trials they composed 75% of our sample. It is important to note that most of these difficult cases actually improved following FootLaser treatment, while three hypertrophic nails accounted for the failures.
Treatment with the PinPointe FootLaser resulted in significant nail clearing in most subjects that was similar in clinical appearance to nail clearing seen with terbinafine when it works. In this regard, our results support the hypothesis that the laser treatment destroys the pathogens that cause onychomycosis.
The current standard of treatment for onychomycosis is pharmacologic. However, drugs require patient compliance, can be toxic and can induce pathogen resistance. This laser treatment does not require daily compliance and, so far, appears to produce no toxicity. In addition to superior safety, the laser treatment promises to be much more effective than drugs. The efficacy of drug therapy is in the range of 15-30% versus 80% efficacy observed in this study. Our results are, of course, preliminary and data from a much larger sample in a well-controlled, multi-center trial is essential to substantiate our findings.
Figure 5. Comparison of the rate of nail plate growth (notch) with nail bed clearing (lesion) shows that the nail plate grows out about twice as fast as the lesion clears.
5. REFERENCES CITED
 Elewski, B.E., Charif, M.A. "Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions," Arch Dermatol 133, 1172-1173 (1977).
 Elewski, B.E., Hay RJ. "Update on the management of onychomycosis: highlights of the Third Annual International Summit on Cutaneous Antifungal Therapy," Clin Infect Dis 23, 305-313 (1996).
 Clayton, Y.M., "Clinical and mycological diagnostic aspects of onychomycosis and dermatomycoses," Clin Exp Dermatol 17(1), 37-40 (1992).
 Ghannoum, M.A., Hajjeh RA, Scher R et al., "A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns," J Am Acad Dermatol 43, 641-648 (2000).
 Crawford, F, Young P, Godfrey C et al., "Oral treatments for toenail onychomycosis: a systematic review," Arch Dermatol 138, 811-816 (2002).
 Elewski, B.E., "A full 'cure' for onychomycosis is not always possible," Arch Dermatol 135, 852-853 (1999).
 Elewski, B.E., "Onychomycosis: pathogenesis, diagnosis, and management," Clin Microbiol Rev 11, 415-429 (1998).
 Gupta, A.K., "Ciclopirox nail lacquer: a brush with onychomycosis," Cutis 68, 13-16 (2001).
 Finch, J.J., Warshaw E.M., "Toenail onychomycosis: current and future treatment options," Dermatol Ther 20, 31- 46 (2007).
 Arrese, J.E., Pierard G.E., "Treatment failures and relapses in onychomycosis: a stubborn clinical problem," Dermatology 207, 255-260 (2003).
 Katz, H.I., "Drug interactions of the newer oral antifungal agents," Br J Dermatol 141(Suppl. 56), 26-32 (1999).
 Grover, C., Bansal S., Nanda S. et al., "Combination of surgical avulsion and topical therapy for single nail onychomycosis: a randomized controlled trial," Br J Dermatol 157, 364-368 (2007).
 Conant, M., "New treatment options for onychomycosis," AIDS Patient Care 9 (Suppl. 1), S19-S21 (1991).
 Lecha, M., Effendy I., Feuilhade de Chauvin M., Di Chiacchio N, Baran R, "Treatment options--development of consensus guidelines. Task force on Onychomycosis Education" J Eur Acad Dermatol Venereol Suppl 1, 25-33 (2005).
 Scher, R.K., Baran, R., "Onychomycosis in clinical practice: factors contributing to recurrence," Br J Dermatol 149 (Suppl 65), 5-9 (2003).
Disclosure: David M Harris and John Strisower are principals of Patholase, Inc. Brian McDowell, DPM is a podiatrist with a private practice in Sacramento, CA.
Lasers and Toenail Fungus
J Am Podiatr Med Assoc. 2010 May-Jun;100(3):166-77
There has been quite a stir in podiatry over the use of lasers to treat toenail fungus. There seems to be a number of studies that show that as the nail temperature approaches 40-50°C (106-122°F) there is inactivation of the fungal spores.
The advantage of laser therapy is that infrared wavelengths lack the teratogenic danger presented by ultraviolet light and the side effects of oral anti-fungal medication.
In this randomized controlled study, they found that 85% of the eligible treated toenails were improved. Of the 16 toes with moderate to severe involvement, 63% were improved, as shown by clear nail growth of at least 3 mm.
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*, Mary Oster,
BS†, and Eric S. Bornstein, DMD†
Journal of the American Podiatric Medical Association May/June 2010, v.100 No.3, 166-177.
*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 02452. (E-mail: email@example.com)
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 periodically during the 180 day follow-up period.
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 eligible treated toenails were improved by clear nail linear extent (P = .0015); 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 = .0112). Simultaneous negative culture and periodic acid-Schiff was noted in 30% at 180 days.
Conclusions: These results indicate a role for this laser in the treatment of onychomycosis, regardless of the 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): 166-177, 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 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 (Boston, Massachusetts). 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.
The idea for this device was stimulated by the discovery by Neuman et al1 that the use of 870- and 930-nm light would kill he microbial specimens they were observed 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 avelengths 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
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 non-contact and contact use by the Food and Drug Administration in podiatric medicine, dermatology, plastic surgery, and otolaryngology, 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/cm2. 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.
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 (ACUDTM; 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 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 the 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. 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.
|Table 1. Study Procedures|
|Baseline||Day 1||Day 14||Day 42 ± 2||Day 60 ± 5||Day 120 ± 10||Day 180 ± 10|
|Culture and PAS staining||X||X||X||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.|
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).
|Table 2. Noveon Laser Factors for the 4- and 2-min Exposures|
|Output Power(W)||Beam Spot(cm)||Area of Spot (cm2)||Time(sec)||Total Energy(J)||Energy Density(J/cm2)||Power Density(w/cm2)|
A non-contact 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 information12 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. Standardized photographs of the toes were taken on the first treatment day (baseline) and on days 14, 42, 120, and 180.
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 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.
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).
|Table 3. Patient Disposition by Study Group|
|Group(n = 26)||ControlGroup(n = 10)||Total(N = 36)|
|Enrolled in the study (No.)a||26||10||36|
|Intention-to-treat population (No.)b||26||10||36|
|Per-protocol (eligible) population (No.)c||25||9||34|
aThe enrolled population includes all of the patients who signed consent forms and were randomized.
bThe intention-to-treat population includes all of the patients who signed consent forms, were randomized, and completed visit 1.
cThe 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|
|Group(n = 44)||ControlGroup(n = 15)||Total(N = 59)|
|No. of intention-to-treat toes||44||15||59|
|No. of all treatable toesa||40||13||53|
|No. of toes eligible to be treated||26||11||37|
aIncludes companion toes, which, per protocol, could be treated but were ineligible to be included in the primary test group because the disease was too extensive or involved the lunula.
Of the 37 toes in the eligible group, only 16% were considered to be purely superficial by the investigators and 38% by the independent panel. 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 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 the 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
The results from the primary study group of 37 toes (Table 4) based on the protocol are presented herein as the “eligible group.” The total of those toes and the companion toes are included herein as the “all-treated group”h (53 toes [40 treated and 13 control]).
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).
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).
Figure 1. Tracking of negative periodic acid-Schiff (PAS) staining in eligible toes with positive PAS staining at baseline. Rx indicates study treatment.
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 an 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).
Figure 2. Eligible toes with negative culture and at least 3 mm of clear nail growth at day 180.
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).
|Table 5. Severity of Disease at Baseline: Eligible Toes|
|Eligible Toes (%)|
|Treated(n = 26)||Control(n = 11)||Total(N = 37)|
|Rating by investigators|
|Rating by independent panel|
|Table 6. Severity of Disease at Baseline: All-Treated Toes|
|All-Treated Toes (%)|
|Treated(n = 40)||Control(n = 13)a||Total(N = 53)|
|Rating by investigators|
|Rating by an independent panel|
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 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 improvements most of the treated toes. However, the degree of difference between the two groups (investigators versus panel) is significant (P = .0092).
|Table 7. Clinical Assessment Compared to Baseline at 180 Days: Eligible Toes|
|Eligible Toes (No. [%])|
|Treated(n = 26)||Control(n = 11)||Total(N = 37)|
|Comparison with baseline by investigator|
|Unchanged or worse||0||2 (18.2)||2 (5.4)|
|Slightly to moderately improved||19 (73.1)||7 (63.6)||26 (70.3)|
|Markedly improved||5 (19.2)||2 (18.2)||7 (18.9)|
|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 improved||18 (69.2)||3 (27.3)||21 (56.8)|
|Markedly improved||1 (3.8)||2 (18.2)||3 (8.1)|
|Completely cleared||1 (3.8)||0||1 (2.7)|
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 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.
Figure 3. Representative treated the case with a mild distal/lateral disease at baseline (A) and after 180 days (B).
Figure 4. Representative treated the case with a moderate superficial disease at baseline (A) and after 180 days (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).
Figure 6. Representative treated the case with mild disease at baseline (A) and with, at most, minimal residual disease after 180 days (B).