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*
Mary Oster, BS†
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
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 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 mi*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 protected])
166
crobial 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 re-
May/June 2010 • Vol 100 • No 3 • Journal of the American Podiatric Medical Association
sponse 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 930nm 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, 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 userprogrammable 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 (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 re-
Journal of the American Podiatric Medical Association • Vol 100 • No 3 • May/June 2010
167
ceive 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 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.
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).
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 30to 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
Table 1. Study Procedures
Baseline
Consent form
Inclusion/exclusion
Randomization
Study treatment
Visual assessment
Culture and PAS staining
Photographs taken
Clear growth measurement
Adverse event recording
Day 1
Day 14
Day 42 ± 2
Day 60 ± 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 120 ± 10
Day 180 ± 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviation: PAS, periodic acid–Schiff.
168
May/June 2010 • Vol 100 • No 3 • Journal of the American Podiatric Medical Association
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)
4-min exposure
870 nm
930 nm
Combined
1.5
1.5
3.0
1.5
1.5
1.5
1.77
1.77
1.77
240
240
240
375
375
750
212
212
424
0.85
0.85
1.70
2-min exposure
930 nm
3.0
1.5
1.77
120
360
204
1.70
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.
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 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,
Energy Density Power Density
(J/cm2)
(W/cm2)
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
26
26
10
10
36
36
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
Treatment Control
Group
Group
Total
(n = 44) (n = 15) (N = 59)
No. of intention-to-treat toes
No. of all treatable toesa
No. of toes eligible to be treated
44
40
26
15
13
11
59
53
37
aIncludes 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.
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 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.
Journal of the American Podiatric Medical Association • Vol 100 • No 3 • May/June 2010
169
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” (53 toes [40 treated and 13 control]).
Mycologic Assessment
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
70 -
Treated
60 -
10 -
50 -
9-
Control
10/26
39%
8-
40 -
730 -
Toes (No.)
Toes with Negative PAS Staining (%)
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).
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).
20 10 -
P = .1192
543-
0Baseline
Day 1
Visit 1
Rx1
Day 14
Day 42
Visit 2
Visit 3
Rx2
Rx3
Topical
Terbinafine
Initiated
Day 60
Visit 4
Rx4
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. Rx indicates study treatment.
170
6-
2-
1/11
9%
10-
Baseline
Day 180
Visit 6
Figure 2. Eligible toes with negative culture and at
least 3 mm of clear nail growth at day 180.
May/June 2010 • Vol 100 • No 3 • Journal of the American Podiatric Medical Association
Table 5. Severity of Disease at Baseline: Eligible Toes
Table 6. Severity of Disease at Baseline: All-Treated Toes
Eligible Toes (%)
Treated
Control
Total
(n = 26)
(n = 11) (N = 37)
All-Treated Toes (%)
Treated
Control
Total
(n = 40)a
(n = 13) (N = 53)
Rating by investigators
Mild
Moderate
Severe
15
46
38
18
45
36
16
46
38
Rating by investigators
Mild
Moderate
Severe
10
38
48
15
38
46
11
38
47
Rating by independent panel
Mild
Moderate
Severe
39
27
34
36
55
9
38
35
27
Rating by independent panel
Mild
Moderate
Severe
30
25
38
31
46
23
30
30
34
a
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
their assessments on actual visual assessments and
Table 7. Clinical Assessment Compared to Baseline at
180 Days: Eligible Toes
Eligible Toes (No. [%])
Treated
Control
Total
(n = 26)
(n = 11)
(N = 37)
Comparison with baseline
by investigator
Unchanged or worse
Slightly to moderately
improved
Markedly improved
Completely cleared
Missing
Comparison with baseline
by independent panel
Unchanged or worse
Slightly to moderately
improved
Markedly improved
Completely cleared
Missing
0
19 (73.1)
2 (18.2)
7 (63.6)
2 (5.4)
26 (70.3)
5 (19.2)
0
2 (7.7)
2 (18.2)
0
0
7 (18.9)
0
2 (5.4)
6 (23.0)
18 (69.2)
6 (54.5)
3 (27.3)
12 (32.4)
21 (56.8)
1 (3.8)
1 (3.8)
0
2 (18.2)
0
0
3 (8.1)
1 (2.7)
0
Photographs from three toes are not available.
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 0.0196 mm per day, clearly lower than the
mean in normal great toes reported by Edwards and
Schott in their classic study.14
Journal of the American Podiatric Medical Association • Vol 100 • No 3 • May/June 2010
171
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).
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.
172
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
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
May/June 2010 • Vol 100 • No 3 • Journal of the American Podiatric Medical Association
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).
nail improvement after treatment. Indeed, the percentage with at least 3 mm of response in those with
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
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.
Journal of the American Podiatric Medical Association • Vol 100 • No 3 • May/June 2010
173
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).
Safety
Cumulatively, 156 treatments were given during the
study. Because each treatment consisted of two expo-
sures (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
Table 8. Clear Linear Nail Growth at 180 Days: Eligible Toes (as Determined by the Independent Panel)
Clear growth (mm)b
<1
1–2
≥3
Mean clear nail growth rate (mm/toe/d) c
Treated (n = 26)
Eligible Toes (No. [%])
Control (n = 11)
Total (N = 37)
4 (15.4)
5 (19.2)
17 (65.4)
0.0196
6 (54.5)
4 (36.4)
1 (9.1)
0.0021
10 (27.0)
9 (24.3)
18 (48.6)
0.0144
P Valuea
.0015
.0167
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.
bCalculated as the difference between clear linear distance at baseline and 180 days.
cGrowth rate = Sum of Clear Nail Growth/No. of Toes/180 Days.
a
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)
Baseline severity
Mild
Moderate
Severe
All
a
Treated
Eligible Toes (No. [%])
Control
Total
7/10 (70)
3/7 (43)
7/9 (78)
17/26 (65)
1/4 (25)
0/6
0/1
1/11 (9)
8/14 (57)
3/13 (23)
7/10 (49)
18/37 (49)
P Valuea
.0112
The P value was obtained with the exact Kruskal-Wallis test.
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May/June 2010 • Vol 100 • No 3 • Journal of the American Podiatric Medical Association
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)
Baseline severity
Mild
Moderate
Severe
All
a
b
Treateda
Eligible Toes (No. [%])
Control
Total
7/12 (58)
4/10 (40)
8/15 (53)
19/40 (65)
1/4 (25)
0/6
0/3
1/13 (8)
8/16 (50)
4/16 (25)
8/18 (44)
20/53 (38)
.0073
Photographic data is not available for three toes.
The P value was obtained with the exact Kruskal-Wallis test.
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.
Discussion
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
Treated (n = 26)
70 -
Control (n = 11)
60 50 Toes (%)
P Valueb
40 30 20 10 0-
Baseline
120 Days
180 Days
Figure 8. Eligible toes with at least 3 mm of clear nail
growth and negative culture.
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.15, 16 Despite the
many options, there continues to be ongoing debate
about the ability to affect 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.17
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
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).18
This rate occurred only after daily oral/systemic administration of these drugs for 3 months or more.
Journal of the American Podiatric Medical Association • Vol 100 • No 3 • May/June 2010
175
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(p1131) 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 severi-
176
ty, 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.20-22
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
and Ms. Oster are employees of Nomir Medical Technologies, Inc, and each has a financial interest in the
company.
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