Laser Treatment for Onychomycosis in Diabetes
Laser Treatment for Onychomycosis in Diabetes
Fungal infections of the toe affect one in three people with diabetes. Current treatments for
 fungal toe infections include oral medications, but these drugs often interact with other
 common medications. We are studying a new treatment for fungal toe infections involving the
 use of a laser device. We will compare to the standard treatment which is a type of
 antifungal medication. This laser has been tested in small numbers of patients with minimal
 side effects. There will be 60 participants selected for our study, of which 30 will receive
 standard treatment and the rest will receive laser treatment.
Onychomycosis is a fungal infection of the nail unit which affects one third of people with
 diabetes.1,2 Risk factors for onychomycosis in diabetes include age, male sex, poor glycemic
 control, longer duration of diabetes, use of immunosuppressive agents, and poor peripheral
 circulation.2-5 Etiology of onychomycosis varies across populations, but the most common
 causes in diabetic patients are yeasts and dermatophytes. In particular, Candida spp.
 (31-48.1%) are the most common yeasts, while Rhodotorula spp. (21.7%) have been reported as
 well.4,6-8 Trichophyton rubrum (31.7-46%) is the most common dermatophyte observed, while
 nondermatophytic molds are less common.

 Individuals with diabetes complicated by peripheral neuropathy are at risk of developing
 particularly severe complications of onychomycosis. Infected nails can become brittle and
 sharp, injuring and compromising the adjacent skin. This breakdown allows a portal of entry
 for bacteria, causing cellulitis and paronychia.9 Because the nail bed is in close proximity
 to the underlying nail, paronychia can develop into osteomyelitis if adequate foot care is
 neglected.

 Given the significant morbidity of onychomycosis including the potential for limb amputation,
 prompt and effective treatment is imperative. Currently available treatments include topical
 and systemic options, and each of these has significant limitations.

 Topical antifungal therapies have been tested in patients with mild onychomycosis. Cure rates
 of 29-85% have been observed with ciclopirox 8% nail lacquer in non-diabetic populations with
 mild disease;10 in diabetic populations using open label methodology cure rates of
 approximately 54% are reported.11,12 Novel topical forms of terbinafine with various
 penetration-enhancing compounds are also under development.13-15 Early studies report
 effective nail penetration of these formulations, but there is a lack of data on clinical
 efficacy of topical terbinafine. One preliminary study reported 90% mycological cure after 12
 weeks of treatment with a terbinafine spray, but less than half had a sustained cure at 36
 weeks post-treatment.16 Although effective for mild to moderate superficial onychomycosis,
 because of poor nail penetration topical agents are generally not recommended where fungus
 appears to infect more than 50% of the nail surface.7 One recent review has suggested that
 monotherapy with topical agents should be avoided altogether.17 Systemic antifungal agents
 are often used to treat more severe onychomycosis. Two of the most common systemic agents are
 itraconazole and terbinafine. Itraconazole is a newer agent with the added advantage of
 covering Candida species in addition to dermatophytes. Both agents are associated with cure
 rates of approximately 50% when given for a full three month course.18 These agents have
 significant limitations given the potential for drug-drug interactions via inhibition of
 cytochrome P450 enzyme subtypes.19 Itraconazole and terbinafine are associated with increased
 risk of bleeding with warfarin, itraconazole with increased risk of rhabdomyolysis with
 statins and of hypoglycemia with oral agents for diabetes and terbinafine with metoprolol,
 propafenone, and tricyclic antidepressants.19 Due to the significant limitations of topical
 and systemic treatments for onychomycosis, there is a critical need for alternative and
 replacement therapies. While surgical techniques such as avulsion and nail plate removal can
 be employed for severe and resistant infections, these treatments are quite invasive and
 painful.7,20 Other device-based therapies for onychomycosis include UV light therapy21-23 and
 photodynamic therapy.24-27 While these modalities show evidence of in vitro efficacy, there
 have been no robust studies conducted yet that demonstrate any clinical effectiveness.

 A promising device-based therapy is laser treatment. The neodymium-doped yttrium aluminum
 garnet (Nd:YAG) device emits a laser in a continuous or pulsed fashion, and the 1064 nm
 wavelength is thought to be optimal due to its ability to penetrate deeply into the nail bed
 to eradicate fungal growth.28 Although this device is approved by the US Food and Drug
 Administration for use in patients with onychomycosis for a "temporary increase in clear
 nail,"28 there is a lack of research demonstrating effectiveness beyond several pilot
 studies. One study demonstrated mycologic cure in 7 out of 8 patients with no major side
 effects aside from temporary nail discoloration and occasional pin prick sensation.29 The
 parameters for the laser included a 0.65 ms pulse duration, 2 mm spot size and 223 J/cm2
 energy fluence, and treatment consisted of 2 to 3 sessions spaced at least 3 weeks apart. A
 Chinese study of 33 patients demonstrated a 51% to 53% cure rate in patients treated for
 eight and four sessions respectively, spaced at 1 week intervals using a 30 ms pulse duration
 and 3 mm spot size laser at 240-324 J/cm2.30 Results from Japan showed a similar cure rate of
 51% in 19 patients treated with 1 to 3 treatments 4 to 8 weeks apart.31 To our knowledge, no
 randomized control trials exist to validate these preliminary findings.

 Study Objectives The objective of this study is to determine the relative safety and clinical
 efficacy of laser treatment using the FOX Nd:YAG 1064 nm device compared to conventional
 therapy (topical terbinafine) in diabetics with onychomycosis of the hallux (great toe).
 Specifically, the study will test the hypothesis that participants randomized to the FOX
 Nd:YAG laser are more likely to be cured 6 months after initiating therapy compared to those
 randomized to conventional therapy. A secondary objective will be to determine the
 improvement in quality of life with laser treatment versus conventional therapy.

 Subjects Eighty participants will be randomized equally to either the laser treatment group
 or the standard care group.

 Study overview

 This is a prospective, randomized, intention-to-treat, non-blinded comparative group clinical
 trial of 80 participants receiving laser or conventional, topical medication, therapy on a
 single infected hallux. All participants will have a baseline and 6 month follow-up visit
 where photographs of the hallux and repeat KOH and culture will be performed.

 Participants randomized to laser group will undergo laser treatment at baseline and be asked
 to return for 2 subsequent visits six weeks apart (at weeks 6 and 12) to undergo further
 laser treatment of the hallux. Each visit will last approximately 45 minutes.

 At the 6-month visit, participants randomized to the control group will be offered the first
 of three laser treatments (the second and third to occur at weeks 30 and 36). Participants in
 the laser group with persistent infections after 6 months will be offered standard therapy.
 No further data will be collected after the final 6-month visit.

 The treatments will be performed at BCDiabetes (400 - 210 West Broadway, Vancouver, V5Y 3W2,
 Canada) owned and operated by Dr. Elliott .

 Primary outcome measures One primary outcome will be the proportion of participants with
 microbiological cure (by KOH and culture) by 6 months post-randomization (i.e.: initiation of
 treatment).

 Other primary outcomes include safety outcomes. Specifically, safety outcomes of interest
 will include the side effects listed below:

 Usual side effect:

 Feeling of warmth, heat, or tingling at the laser target site (only during treatment)

 Rare side effects:

 Discoloration/burn marks on surface of the nail Slight or mild pain (only during treatment)
 Redness of the treated skin around the nail (lasting 24-72 hours)

 Rare laser effect:

 Sometimes the laser creates 'sparks' on the surface of the nail - this does not cause any
 problems

 Extremely rare laser effects Blistering of the treated skin around the nail Scarring of the
 treated skin around the nail

 Secondary outcome measures Secondary outcomes will include the proportion of participants
 experiencing clinical cure by visual assessment (planimetry and photograph) will be
 evaluated.

 The other secondary outcome will be improvement in quality of life as measured by the
 validated "NailQoL" questionnaire which assesses symptom, emotion, and functional domains.

 Recruitment Patients ostensibly meeting the study inclusion and exclusion criteria seen in an
 outpatient setting by the authors and their associates and staff will be apprised of the
 availability of a research treatment for fungal toenail infection. The study will be briefly
 described - patients who express an interest will be provided additional information and a
 study consent form and be encouraged to ask questions about the study. They may choose to
 provide consent at the time or to leave with the consent form and return at a later time to
 ask further questions.

 The anticipated accrual will be 80 patients in total. Screening Patients will participate in
 a screening visit as part of routine care. Informed consent will be obtained before any
 screening procedures. During this visit, toenail clippings will be sent for KOH stain and
 fungal culture. The results of these tests will be available in approximately 4 weeks. The
 results will be reviewed 6 weeks after the clippings are collected, and if the results are
 negative the patient will be excluded from study.

 Patients positive for both KOH and fungal culture will be eligible for further screening with
 both ankle-brachial index evaluation and biothesiometry, and this screening would occur
 during the same visit.31-33 Patients with an ankle-brachial index less than 0.6 or
 biothesiometry score of less than 20 volts in either lower extremety will be excluded from
 participation as described in the exclusion criteria.

 Samples will be collected only from the infected hallux, and if the hallux from both feet
 appear to be infected, samples from both feet will be taken and sent for analysis. If both
 right and left hallux samples are positive, one hallux will be chosen at random to be treated
 as part of the study.

 Intervention Group Treatment Procedures

 Laser energy (1064 nm Nd:YAG) will be delivered via an optical fibre (300 μm core/320 μm
 clad) secured in a hand piece. Laser energy will be delivered by maintaining the tip of the
 optical fibre 3 mm from the treatment area to achieve around 1-1.5 mm diameter spot size
 (25.5 J/cm2 fluence per pulse; 10-pulse pulse-train to each spot in 0.5 seconds). Multiple
 treatment spots will be delivered to cover the entire area of involvement. Treatments cause
 no discomfort and are administered as an outpatient service with no anesthesia. If the
 subject experiences significant discomfort, the procedure may be interrupted for up to 5
 minutes to allow the discomfort to subside.

 The FOX laser will be used in accordance with manufacturer recommendations, with output
 power, spot size, and proprietary pulse train incorporated into the treatment regimen.
 Treatment will take place by traversing the infected hallux in a side to side fashion, with
 care being taken to cover the entire surface of each nail, by slightly overlapping the
 previous path. In areas where the nail appears to be infected, a second series of passes
 perpendicular to the first set will be performed, again slightly overlapping the previous
 path, as described above. Even if other toes in addition to the hallux appear to be infected,
 only one hallux per participant will be treated and analyzed for the purposes of the study.
 The treatment will be performed as an outpatient procedure at St. Paul's Hospital or Mount
 St. Joseph's Hospital.

 Participants who fail to return for a scheduled treatment will be asked to return for another
 treatment as soon as possible. The schedule for subsequent treatments will be readjusted
 based on the completion date of the missed visit.

 Control Group Treatment Procedures

 Participants in the control group will be treated conventionally with terbinafine HCl
 external ointment.

 Planimetry Procedures

 Photographic documentation and assessment of the treated toenails will be done at the
 interval visits as listed in the subject follow-up table below. The extent of mycological
 involvement will be determined by measuring the mm of clear nail from the cuticle line to the
 demarcation of clinically involved nail. This data will be recorded in the case report form.
 Nails are scored (grooved) at the initial visit to indicate the most proximal level of
 involvement. The distance from the proximal cuticle to the scored mark will be measured at
 each visit on any involved hallux nail.

 The photograph will be analyzed using ImageJ software version 1.4.1 ( HYPERLINK
 "http://rsb.info.nih.gov/ij/docs/intro.html"http://rsb.info.nih.gov/ij/docs/intro.html), a
 public domain Java image processing program inspired by NIH Image written by Wayne Rasband (
 HYPERLINK "mailto:wayne@codon.nih.gov"wayne@codon.nih.gov), Research Services Branch,
 National Institute of Mental Health, Bethesda, Maryland, USA. The software will be used by an
 expert PathoLase photo-evaluator to measure the linear distance of non-involved toenail
 (e.g., clear of infection) immediately before treatment (baseline) and 6 months.

 Withdrawal and End of Participation

 A participant is free to withdraw from the study at any time, for any reason without
 prejudice to their future medical care by the physician or at the institution. The
 Investigator also has the right to withdraw participants from the study in the event of
 intercurrent illness, adverse events, administrative, or other reasons unrelated to the study
 if such a decision is in the subject's best medical interest.

 When a participant withdraws from the study, all assessments required at the 6-month study
 visit will be obtained, where possible. All details available will be reported and recorded
 for any subject who withdraws from the study. Participants, who wish to withdraw from
 treatment, will be encouraged to return for their 6-month study visit to complete the
 required examination.

 If a participant is lost to follow-up, at least 3 documented attempts must be made to contact
 the subject, one of which must include sending a certified letter to the participant's last
 known address, which includes a request to return to the study site for final study
 evaluations.

 Participants who fail to return for their 6-month visit will be considered failures (i.e. no
 microbiological cure) unless a nail clippings were obtained from a prior visit and confirmed
 as microbiological cure.

 Information on whether microbiological cure was achieved during the study will be shared with
 subjects as well as their health care providers.

 At the completion of study procedures, laser treatment will be offered to control group
 participants as well as to intervention group participants who wish to have additional toes
 treated.

 Risks and Discomforts The following is a list of risks and possible discomforts associated
 with the FOX Nd:YAG 1064 nm laser. Precise estimates of the percentage occurrence of these
 side effects are not available given the limited number of pilot studies available.

 Usual side effect:

 Feeling of warmth, heat, or tingling at the laser target site (only during treatment

 Rare side effects:

 Discoloration/burn marks on surface of the nail Slight or mild pain (only during treatment)
 Redness of the treated skin around the nail (lasting 24-72 hours)

 Rare laser effect:

 Sometimes the laser creates 'sparks' on the surface of the nail - this does not cause any
 problems

 Extremely rare laser effects (did not occur during clinical studies):

 Blistering of the treated skin around the nail Scarring of the treated skin around the nail

 Significant side effects were not reported in several small pilot studies of the Nd:YAG 1064
 nm laser. We will minimize the risk of side effects by using the laser strictly according to
 the manufacturer-recommended protocol described in the intervention section above. We would
 consider stopping the study early if severe side effects such as blistering and scarring are
 unexpectedly observed in a significant proportion of study participants.

 Side effects for the control group receiving topical terbinafine are to be expected as part
 of the current standard of care. The known side effects of this conventional treatment are
 detailed as below:

 Dermatologic side effects (1-10%): Burning, contact dermatitis, dryness, exfoliation,
 irritation, pruritus, rash Local side effects (1-10%): Irritation, stinging Statistical
 Analysis

 Analysis Supporting the Primary Objective

 The primary outcome measure is the proportion of participants with microbiological cure (by
 KOH and culture) by 6 months post-baseline treatment. The null and research hypotheses
 supporting the primary objective of investigating the impact of whether laser treatment,
 using the FOX Nd:YAG 1064 nm device, is more effective in the treatment onychomycosis in
 comparison to conventional therapy (topical terbinafine) is then:

 H0: pc ≥ ptr vs. H1: pc < ptr where pc and ptr are the proportion of subjects with
 microbiological cure (by KOH and culture) by 6 months post-baseline treatment, within the
 control group, and the laser group respectively. Here, rejecting the null hypothesis implies
 that the proportion of participants achieving microbiological cure is higher in the laser
 group. A 1-sided, 0.05 alpha-level Fisher's exact test for proportions will be used.34

 The rate of each safety outcome (feeling of warmth/heat/tingling, discolouration or burn
 marks, pain, redness, sparks, blistering, scarring), and accompanying 95% exact binomial
 confidence interval, will be calculated.

 Sample Size Considerations

 Based on previous studies, terbinafine may be associated with cure rates of approximately 50%
 (when given for a full three month course).18 The success rate of the FOX laser group has not
 been thoroughly investigated. Table 2 provides the power to detect various true differences
 between the control and laser groups where the control group is assumed to have a success
 rate between 40% and 60%. A sample size of 80 subjects in a 1:1 randomization to the control
 and laser arm will provide a power of 80% to reject the null hypothesis if the laser arm true
 cure rate in the control arm is 79% and the control arm is achieves a cure rate of 50%. If
 the success rate in the control group is as high as 60%, a difference of 26% between the
 groups will be detectable with 80%. If the true difference is 34% or greater, it will be
 detected with at least 90% power. For a total sample size of 100, a true difference of at
 least 31% will be detectable with at least 90% power, a reduction of only 3%. Similarly, for
 a total sample size of 60, the difference must be at least 39% to be detected with at least
 90% power, an increase of 4%.

 Human Subjects Protection This study will be conducted in accordance with the ethical
 principles originating from the Declaration of Helsinki and Good Clinical Practices (GCP)
 defined in ICH E6 and in compliance with provincial and national regulatory requirements.

 Justification for exclusion of children

 Justification for exclusion of other vulnerable subjects (Vulnerable subjects include who
 lack consent capacity, mentally ill, prisoners, cognitively impaired subjects, pregnant
 women, etc.

 Justification of sensitive procedures Our study does not involve the use of placebo,
 medication withdrawal, provocative testing, or deception.

 Safeguards for vulnerable populations:Females of childbearing potential must agree to
 practice sexual abstinence or use a medically acceptable method of contraception for the
 duration of the study and for at least 1 month after the last day of test article
 administration Anticipated Benefit Study participants randomized to the medication group will
 receive the current best available treatment for onychomycosis. Participants who fail to be
 cured by this treatment will have the option to undergo treatment with the laser following
 the 6 month study visit. It is possible that participants randomized to the laser treatment
 will be more likely to be cured than the standard treatment.

 Consent documents and process All subjects for this study will be provided with a consent
 form describing this study and providing sufficient information for subjects to make an
 informed decision about their participation in this study. This consent form will be
 submitted with the protocol for review and approval by the REB for the study. The formal
 consent of a subject, using the REB approved consent form, must be obtained before that
 subject undergoes any study procedure. The consent form must be signed by the subject or by a
 legally acceptable surrogate, and the Investigator and/or designated research professional
 obtaining the consent. A copy of the signed and dated informed consent form must be given to
 the subject and the consent process must be documented.

 Quality Assurance Before enrolling any subjects in this study, the Investigator and other
 staff will review the protocol, the source documents and instructions for their completion,
 the procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs.

 Collected data will be reviewed for completeness on a monthly basis and include a review of
 missing data elements, missing or out-of-window visits, and any other anomalies.

 Adverse event and unanticipated problem reporting

 Adverse Events

 An adverse event (AE) can be any unfavourable and unintended sign, symptom, or disease
 temporally associated with the use of an investigational product. The event does not need to
 be causally related to the test article or clinical study. An AE includes, but is not limited
 to, the following:

 Any clinically significant worsening of a pre-existing condition. An AE occurring from
 overdose of a test article, whether accidental or intentional. Overdose is a dose greater
 than the dose (i.e. laser intensity) specified for each test article in section 4.2.

 An AE occurring from abuse (e.g., use for nonclinical reasons) of a test article.

 An AE that has been associated with the discontinuation of the use of a test article.

 The severity of all adverse events is graded as follows:

 Mild

 Signs or symptoms, usually transient, requiring no special treatment and generally not
 interfering with usual activities

 Moderate

 Signs or symptoms, which may be ameliorated by simple therapeutic measures, may interfere
 with usual activity.

 Severe

 Signs or symptoms that are intense or debilitating and that interfere with usual activities.
 Recovery is usually aided by therapeutic measures and the discontinuation of the study device
 may be required.

 The relationship of each adverse event to the study was defined as follows:

 Probable

 An adverse event has a strong temporal relationship to study device, and another etiology is
 unlikely or significantly less likely.

 Possibly

 An adverse event has a strong temporal relationship to the study device, and an alternative
 etiology is equally or less likely compared to the potential relationship to study device.

 Not related

 An adverse event has no temporal relationship to study device or has a much more likely
 alternative etiology.

 Serious Adverse Events

 A serious adverse event (SAE) is an AE that:

 Results in death; Is life-threatening, i.e., an event that places the subject, in the view of
 the Investigator, at immediate risk of death from the event as it occurred (does not include
 an event that, had it occurred in a more severe form, might have caused death); Requires
 inpatient hospitalization or prolongation of an existing hospitalization; Results in
 persistent or significant disability or incapacity; Results in cancer; Results in a
 congenital anomaly or birth defect; Other medically important events that in the opinion of
 the Investigator may jeopardize the subject or may require intervention to prevent one of the
 other outcomes listed in the definition above; Any serious problem associated with the device
 that relates to the rights, safety or welfare of study subjects.

 Reportable Incidents

 According to the Canadian Medical Devices Regulations (Sections 59 and 81), a reportable
 incident is any incident that:

 Is related to a failure of the device or a deterioration in its effectiveness, or any
 inadequacy in its labeling or in its directions for use; and Has led to the death or a
 serious deterioration in the state of health of a participant, user or other person, or could
 do so were it to recur.

 Efficacy Endpoints and Disease Progression Event

 In general, an event of treatment failure or lack of treatment efficacy is not considered an
 SAE. If, however, it results in a situation that qualifies as an SAE as defined above, it
 should be reported. Treatment failure/lack of efficacy will be captured on the clinical
 evaluation source documents and, if it results in discontinuation of test article or
 withdrawal from the study, should be captured on those source documents as well.

 Recording of Adverse Events

 At each contact with the subject, the Investigator will seek information on adverse events by
 specific questioning and, as appropriate, by examination of the subject. Information on all
 adverse events should be recorded immediately. All clearly related signs, symptoms, and
 abnormal diagnostic procedure results should be recorded, though should be grouped under one
 diagnosis.

 All adverse events occurring during the study period must be recorded. The clinical course of
 each event should be followed until resolution, stabilization, or until it has been
 determined that the study treatment or participation is not the cause.

 Confidentiality

 Information about study subjects will be kept confidential and managed according to the
 requirements of the Federal and Provincial Data Protection regulations, including the
 Personal Information Protection and Electronic Documents Act (PIPEDA 2000). Those regulations
 require signed subject authorization, informing the subject of the following:

 What protected health information (PHI) will be collected from subjects in this study; Who
 will have access to that information and why; Who will use or disclose that information; The
 rights of a research subject to revoke their authorization for use of their PHI.

 In the event that a subject revokes authorization to collect or use PHI, the Investigator, by
 regulation, retains the ability to use all information collected prior to the revocation of
 subject authorization. For subjects that have revoked authorization to collect or use PHI,
 attempts should be made to obtain permission to collect at least vital status (i.e. that the
 subject is alive) at the end of their scheduled study period.

 Data Access

 Data will be stored in electronic medical records within the clinical practice. Data will be
 accessed only by study investigators or the study statisticians. Individual level data will
 be identified only with study registration numbers.

 Records Retention

 The Investigator shall retain and preserve electronically all data generated in the course of
 the study, specifically including but not limited to those defined by GCP as essential for 25
 years from the date of the completion of the study.

 Conflict of Interest Study investigators have no financial interests relating to the laser or
 medication arms of these studies.
Inclusion Criteria:

 -  Provides full informed consent to participate in the study;

 -  At least 19 years of age;

 -  Established diagnosis of diabetes mellitus at the time of screening for the study
 according to Canadian Diabetes Association (CDA) criteria;

 -  Clinically assessed to have subungual onychomycosis (fungal infection of the nail) of
 the hallux, confirmed by KOH and culture performed at the screening visit.

 Exclusion Criteria:

 -  Presence of necrotizing fasciitis, cellulitis, wet gangrene, gas gangrene, erythema
 gangrenosum, or psoriasis;

 -  Presence of peripheral arterial disease defined as an ankle-brachial index less than
 0.6 on either lower extremity;

 -  Presence of peripheral neuropathy defined as a biothesiometry score of less than 20
 volts on either lower extremity;

 -  Treatment with oral terbinafine (Lamisil), itraconazole (Sporanox), or griseofulvin
 within 12 months of the proposed study start date;

 -  Treatment with any topical antifungal medications including ciclopirox, itraconazole,
 or other over-the-counter remedies for toenail infection within 1 month of
 randomization;

 -  Female of childbearing potential who does not agree to practice sexual abstinence or
 use a medically acceptable method of contraception for the duration of the study and
 for at least 1 month (30 days) after the last day of test article administration; (A
 woman of childbearing potential is one who is biologically capable of becoming
 pregnant; this includes women who are using contraceptives or those women whose sexual
 partners are either considered sterile or using contraceptives.)

 -  Has a physical disability or psychiatric diagnosis which would limit the ability to
 adhere to the study regimen, as judged by the Investigator;

 -  Is a prisoner, or is in pre-trial;

 -  Is known to be without a fixed address;

 -  Has documented evidence of a history (e.g. liver testing) of substance abuse within
 the 12 months prior to screening for study entry;

 -  Is a Workers Compensation Board (WCB) patient;

 -  Is unable to easily communicate in oral and written English.