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Methods of Enquiry Dissertation: Modified photodynamic therapy treatment for toenail onychomycosis in adults: study protocol for a randomised controlled trial

Word Count

Pages 4-16 (up to “Trial Status”) 4,843 words

Less tables and headings 741 words

Revised word count 4,102 words

Within 10% allowance of the 4,000 word limit

Not including pages after “Trial Status” i.e. reference list, figures and appendices

Competing interests

The author declares that he has no competing interests.

Authors’ Contribution and Acknowledgements

This manuscript was prepared as a Methods of Experimental Design (MoED) dissertation

towards a BSc Podiatry Degree at the University of Salford. The author gratefully

acknowledges the University of Salford and his supervisor, Dr Andrew H. Findlow, for his

expert supervision, advice and support.

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Table of Contents

Table of Contents ....................................................................................................................... 2

Abbreviations ............................................................................................................................. 3

1. Introduction .................................................................................................................... 4

1.1 Aims and objectives .................................................................................................... 4

1.2 Topic justification ....................................................................................................... 5

2. Literature review and background ................................................................................. 6

3. Methodology and data collection ................................................................................... 9

3.1 Mycological Examination – Microscopy & Microbiological Analysis .................... 11

3.2 Initial nail curettage or drilling.................................................................................. 12

3.3 Photodynamic therapy (PDT) intervention ............................................................... 12

3.4 Clearanail therapy intervention ................................................................................ 13

3.5 Combined Treatment – Clearanail and PACTMED

+ PACT Nail Fungus Gel ........... 14

3.6 Calculation and sample size ...................................................................................... 14

3.7 Outcome Measures .................................................................................................... 15

3.8 Hypothesis ................................................................................................................. 15

3.9 Organisation and statistical analysis of data ............................................................. 16

4. Discussion .................................................................................................................... 16

4.1 Trial Status ................................................................................................................ 16

5. References .................................................................................................................... 18

5.1 Websites .................................................................................................................... 18

5.2 Papers ........................................................................................................................ 18

6. Attachments ................................................................................................................. 22

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Abbreviations

PDT: Photodynamic Therapy

PS: Photosensitiser

PACT: Photodynamic Antimicrobial Therapy

PACTMED

: PACTMED

630nm laser system (Hahn Medical Systems)

MB: Methylene Blue

TB: Toluidine Blue

LED: Light Emitting Diode

SA: Surface Area

ROS: Reactive Oxygen Species

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1. Introduction

Topical antifungals may be able to treat minor superficial fungal nail infections, but the

majority of presenting fungal nails involve a full thickness lesion against which topical

antifungals struggle to be effective. Recently, a new device, Clearanail, has been developed

which safely drills 0.4mm holes into the nail plate, allowing antifungal treatments direct

access the nail bed (Richards, 2015). A number of case studies have reported effective

treatment using the Clearanail device, with visible results claimed within two to eight weeks,

and resolution from 3 months. Prior to Clearanail arriving on the market in 2015, the other

device widely advertised for the safe treatment of fungal nails was the commercially

available PACTMED

(Photodynamic Antimicrobial Therapy) LED laser (figure 1). The

PACTMED

system claimed to combat fungal infections with a single treatment or repeated

treatments over a week, with effectiveness being apparent at approximately three months

once the affected nail has had chance to grow out (Hahn Medical Systems, n.d.). However,

there are no full scale clinical trials evaluating these two devices and their effectiveness in

treating toenail onychomycosis.

1.1 Aims and objectives

This study proposes to evaluate both PACTMED

and Clearanail, and a combined treatment to

see if enhanced efficacy and clinical cure rate can be achieved. Table 1 describes the thought

process from the initial hypothesis, to considering the problem and the population involved,

to the intervention groups proposed and the outcome measures.

Table 1 - Defining the research question

Initial Hypothesis:

Do nail plate perforations significantly improve the absorption of the photosensitising (PS) agent?

General nature of the problem:

In older people who may not be suitable for oral antifungal treatments, due its side effects or drug-drug

interactions, can we find a non-systemic treatment that can effectively treat fungal nails?

Population:

People with fungal nails, affecting up to 28% of adults over 60 years of age (Gupta, et al., 1997).

Intervention:

Group 1: PACTMED photodynamic therapy using PACT-Nail Fungus Gels (PS agent)

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Group 2: Clearanail treatment followed by topical antifungal treatment – Lamisil spray

Group 3: Combined treatment of Clearanail perforations with PACTMED

PDT

Outcome:

Measure clinical outcome at 12 weeks (3 months) to 48 weeks (11 months), thus requiring at least 12 weeks for

the onychomycotic nail to begin to grow out, with eukaryotic nail developing – hopefully showing clearance

from fungus.

Outcome measures could involve looking at: nail regrowth (total, partial, or no clearance from fungus); fungal

cure rate (visual and mycological testing at 48 weeks); satisfaction (questionnaire); reduction in discomfort

(questionnaire); reduction in pain and improved mobility (questionnaire).

1.2 Topic justification

Generally, the NHS does not offer alternative non-systemic anti-fungal nail treatments for the

elderly or for those for whom oral or topical antifungals would either be ineffective or would

pose too much risk in terms of side effects (gastrointestinal disturbances, headache, change in

taste), and systemic antifungals have the potential to affect liver function (United States

National Library of Medicine, n.d.). Often with the elderly, fungal nails are simply managed

with appropriate cutting and filing, but a problem arises when they are not managed

appropriately and they become dystrophic and hyperkeratotic. This can cause pressure

leading to discomfort, possibly pain and reduced mobility, and may lead to ulcers and create

a wound as a site for infection. A recent study involving 150 subjects with fungal toenails

found that 54% had toenail discomfort, whilst 36% reported pain on walking which limited

mobility (Lubeck et al., 2014).

Fungal nails affect up to 28% of the population over the age of 60 (Gupta, et al., 1997), and

as a significant proportion of this population then goes on to suffer discomfort and pain from

their dystrophic hyperkeratotic nails, there is a clear need for an effective antifungal treatment

that will be suitable for patients who otherwise would not be candidates for oral anti-fungal

treatment, including the immunocompromised and the elderly with contraindications.

The PACTMED

system offers a simple and safe device that can be used with a photosensitiser

(PS) to target and treat onychomycotic toenails. As a specific wavelength of light is used (630

nm), there is no risk of heat generation, and the fungicidal effect is from the creation of ROS

within the tissue itself, rather than by heat destruction as with thermolytic lasers.

The Clearanail device safely perforates the nail plate allowing access to the nail bed, and

provides a useful port of entry to target fungal nail infections, vastly improving the surface

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area available for treatment (see Appendices 1A and 1B). Case studies using Lamisil spray or

gel over a Clearanail perforated nail plate have reported successful clearing of toenail fungus

(Mason, 2015a; 2015b).

PDT in the PACTMED

system provides a useful antifungal tool to treat toenail onychomycosis.

The development of PDT continues today, and there are a number of different photodynamic

therapies available, ranging from treating cancerous cells (Brown, Brown, & Walker, 2004;

Shafirstein et al., 2015; Bahner & Bordeaux, 2013), to use in dental surgery to treat infected

root canals (‘Cumdente – Photoactivated therapy’, n.d.; Konopka & Goslinski, 2007; Gursoy,

et al., 2012). There are also further developments with PS dyes linked to antibodies or

antibody fragments for very specific targeted PDT (Drobizhev et al., 2006; Renno et al.,

2004).

2. Literature review and background

PDT in one of earliest forms of photo-medicine and can be traced back some 3,000 years to

ancient Egypt where an extract from the plant Ammi majus containing the furanocoumarin

compound psoralem was used on the skin to induce a beneficial photoreaction in sunlight to

help cure various skin aliments (Hamblin & Huang, 2013). From the 18th

Century onwards,

the benefits of light therapy or sunbathing were described for several conditions, including

rickets. The first reported PDT discovery was made in 1900 by Rabb, a medical student in

Munich, Germany, and von Tappeiner. They found that the combination of the dye acridine

red and light exposure, killed infusoria. By 1907, the term ‘photodynamic action’ was used to

describe the use of a PS dye being activated by light to cause a beneficial cytotoxic effect

(ibid).

PDT uses ROS produced by a non-toxic PS, activated by red/blue low intensity light to cause

a cytotoxic effect against microbial cells, cancer cells, and fungi, but leaving the majority of

healthy mammalian cells intact. Mammalian cells are more resistant to the ROS and singlet

oxygen molecules produced by PDT.

The photochemical process is concerned with matching light of the appropriate wavelength to

the absorption band of the PS dye. By matching these two elements, the applied light at that

specific wavelength is 100 times more intense without becoming hot. By comparison, white

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light would generate heat if the intensity was increased 100 fold. In PDT this filtered

wavelength of light, specific to the dye or PS used, gives sufficient photon energy to the

absorbed PS molecule, exciting it into a triplet state which can then transfer energy to ground

state oxygen molecules present in tissue, and excite the oxygen into a singlet state or ROS

(Castano, Demidova, & Hamblin, 2004). Figure 2 (page 24) illustrates the photochemical

mechanism in PDT, and Figure 3 (page 25) illustrates the fungal cell wall structure that is

destroyed by ROS/singlet oxygen by oxidative cross-linking and fragmentation of the

proteins within the fungal cell wall (Kharkwal, et al., 2011).

The excited PS triplet state can cause two types of reaction within the normal physiological

oxygen molecules present within the tissue:

1. Type I reaction – superoxide or ROS – cytotoxic to microbial cells and host cells.

2. Type II reaction – singlet oxygen – cytotoxic to microbial cells and host cells.

A simplified mode of action is presented in Table 2:

Table 2 - Simplified mode of action

PS molecule absorbed into tissue e.g. toluidine blue – inactivate i.e. ‘Ground state PS molecule’

Photon energy is absorbed from the specific wavelength of the light source used

This photon energy causes the PS molecule to become excited into a state referred as – ‘first excited singlet state

PS molecule’

Then as the singlet PS molecule slightly loses a bit of energy by fluorescence or by intersystem crossing - where

there is a change in the spin of an electron, i.e. by slight loss of energy the excited PS molecule enters into a

third more stable excited state, the ‘PS triplet state’.

It is this PS triplet state that gives rise to ROS type I (superoxide O2-) and type II (singlet oxygen

1O2) reactions.

Singlet oxygen as a result of the type II reaction - is widely believed to be the major damaging species in PACT

(Donnelly, McCarron, & Tunney, 2008; Konan, Gurny, & Allémann, 2002)

The fungal cell wall is made up is made of a plasm membrane coated by a thick layer of beta-

glucan and chitin which acts as a permeability barrier making it more difficult for the PS to

bind. It is common for a permeabilising agent such as EDTA (ethylenediaminetetraacetic

acid) to be used with the PS, but other mechanisms can be used such as imparting a cationic

charge to the PS molecule to improve absorption (Valduga, et al., 1993). PS agents that have

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been used in clinical studies, include: phenothiazinium dyes such as methylene blue (MB)

and toluidine blue (TB); porphyrins such as aminolevulinic acid (ALA) and

methylaminolevulinate (MAL); and heamatoporphyrin derivatives, such as neutral red,

indocyanine green, chlorophyll, and polyethyleneimine chlorin(e6) conjugate (PEI-ce6

conjugate). There are also endogenous porphyrins, for example those naturally produced by

the most common acne-causing bacterium Propionibacterium acne, which allow PDT

therapy to treat acne without the need to apply any additional PS agent (Elman, Slatkine, &

Harth, 2003). There is a wider range of PS agents which may have better properties but

would require FDA approval for human clinical trials, but further PS advances are being

made. For example, Osmium (II) is a biquinoline-based PS able to absorb light at

wavelengths throughout the green, red, and near infrared spectrum, allowing selective

activation to destroy cancerous targets at a wide range of tissue depths (Fleck, 2015). In

respect of the PACTMED

system which operates at 630nm, it has been reported that this

wavelength achieves a penetrative depth in the order of 1-3mm, and that increasing the

wavelength to 700-850nm can double the penetrative depth (Svaasand, 1984; Wilson, Jeeves,

& Lowe, 1985), but for oxidative action, the tissue needs to absorb the PS molecule to the

appropriate depth for activation.

Toenail fungus can affect up to 10% of the population with a 28% incidence in those over 60,

and it would not be uncommon for a podiatrist to see at least 2-3 patients every day who are

affected by onychomycotic toenails. Several studies have been conducted using PDT to treat

affected toenails with varying degrees of success. Souza et al. (2013) compared 40 patients

undergoing PDT with methylene blue (MB) as the PS and another 40 patients using an oral

fluconazole treatment. The inclusion criteria included having a positive mycological

examination confirmed by direct microscopic examination of the subungual material, or by

confirmation of positive cultures. The cohorts were further subdivided into those with

significant subungual hyperkeratosis (>2mm) requiring nail filing or curettage prior to PDT

(the ‘realised’ group), and those with nail thickness of ≤2mm who did not (the ‘unrealised’

group). Following PDT treatment lasting 24 weeks, and after a further 24 weeks, there was a

90% clinical cure rate in the MB-PDT patients with nail thickness ≤2mm (unrealised)

compared to a 78% clinical cure rate with patients with nail thickness originally >2mm and

having been subject to curettage (realised). When compared to the group taking fluconazole,

the author reported a 46% cure rate in patients with nail thickness ≤2mm. The 90% clinical

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cure rate had actually been 100% at week 24, and is assumed that by week 48, 10% of those

patients had become re-infected. MB-PDT treatment had no systemic adverse events or

photo-toxicity reactions (ibid; Heyes, 2015).

In a separate study, Souza et al. (2014) looked at MB PDT therapy over a 6-month period

(treatment was given at 15 day intervals) of 22 patients, 11 of whom had severe toenail

onychomycosis. In all patients, Trichophyton rubrum was confirmed by mycology and none

had used any antifungal medication in the previous four months. The severe onychomycotic

cases had nail curettage and filing performed prior to treatment. In patients classed as having

mild to moderate onychomycosis, a 100% clinical cure rate was observed at 48 weeks and a

64% clinical cure rate was observed in the severe onychomycotic group. Again this

confirmed that MB PDT produces a favourable outcome, with 18 out of 22 patients having

achieved a clinical cure and with no adverse effects reported (ibid; Heyes, 2015).

A further study using a less intensive regime of PDT treatment was conducted by Tardivo et

al. (2015). They used a MB:TB-PDT therapy, repeated monthly. Results were based on visual

appearance at the end of the treatment session, being classed as complete clearance, partial

clearance, or no change. It was found that using this monthly PDT regime resulted in 28

patients (45%) showing complete clearance, 25 patients (40%) showing partial clearance, and

9 (15%) showing no change. The average number of sessions required for those patients to

achieve 100% clearance was 5. This compared favourably with other PDT regimens requiring

bi-weekly treatments over a 6-month period. The clinical cure rate was still good, and was

comparable to that achieved with oral antifungal medication. However, this study was based

purely on observational findings (Tardivo, Wainwright, & Baptista, 2015; Heyes, 2015).

3. Methodology and data collection

This study will comply with regulations governing research involving human subjects, and

approval will be sought from the Research Ethics Committee of the University of Salford.

The study will be registered with ClinicalTrials.gov, or an International Standard

Randomised Controlled Trial Number (ISRCTN) will be obtained in accordance with the

Research Governance Framework (England). Participants will be informed of the procedures

and will be asked to sign a statement of informed consent.

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Male and female patients enrolled at the University of Salford Podiatry Clinic will be

recruited for the study. Those aged between 40 and 80 years with visual distal and lateral

subungual toenail onychomycosis and having a positive mycological diagnosis for toenail

onychomycosis will be included. The inclusion and exclusion criteria (see Table 3) excludes:

patients with non-healed foot or plantar lesions; those with non-healed leg ulcers; those

undergoing cancer treatment; those having had antibiotic therapy in the last month; those who

are pregnant; and those with a known hypersensitivity to toluidine blue (PACT Fungal Nail

Gel) and 10% urea cream) or Lamisil antifungal spray. As this is a randomised clinical trial,

the recommendations of the Consolidating Standards of Reporting Trials (CONSORT) will

be used to ensure greater transparency and quality (see Figure 4). For ethical considerations,

risk analysis, scope and limitations, see Appendices 2, 3 and 4. A further research question is

presented in Appendix 5, and the pros and cons of PDT are broadly considered in Appendix

6.

Table 3 - Inclusion / exclusion criteria

Inclusion Criteria:

Male and female adults aged 60 ± 20 years of age enrolled at the podiatry clinic of the University of Salford

Patients diagnosed positively for toenail onychomycosis:

1. POSITIVE Qualitative Examination i.e. presenting with clinical signs of onychomycosis –

discolouration / dystrophy of the nail plate / subungual debris / or onycholysis

2. POSITIVE Microscopic examination of the subungual material with 20% potassium hydroxide to

confirm the presence of fungal hyphae

3. POSITIVE Culture using Sabouraud agar gel with chloramphenicol and cycloheximide to identify the

presence of fungi

Exclusion Criteria:

Patients with nail changes because of skin disease or associated systemic disease

Patients who have undergone oral antifungal medication within the last 6 months

Patients undergoing any other current podiatry treatment e.g. corrective surgery or ongoing verrucae treatment

etc.

Patients with any osteomyelitis or gout trophi

Patients with any open or unhealed foot or lower leg lesions

Patients undergoing any cancer treatment (i.e. if receiving PDT therapy for cancerous lesions – the patient may

already have been injected with a photosensitiser)

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Patients under any current antibiotic treatment or having taken antibiotics within the last month

Female patients currently pregnant

Patients with any known hypersensitivity or allergy to the photosensitiser

3.1 Mycological Examination – Microscopy & Microbiological Analysis

Clinical signs of toenail onychomycosis (nail dystrophy, discolouration, onycholysis,

subungual debris, hyperkeratosis, and ridges) will be confirmed by microscopic examination

of the subungual matter with 20% potassium hydroxide (with blue or black dye) to confirm

the presence of fungal hyphae. Culture will be performed using nail curettage on Sabouraud

agar with chloramphenicol and cycloheximide to isolate Trichophyton and Candida species.

Positive microbiological analyses should confirm that the majority of the fungal infections

are caused by Trichophyton rubrum, Trichophyton mentagrophytis or Candida albicans.

Table 4 confirms that treatment groups 1, 2 and 3 will be comprised of patients presenting

with onychomycosis as identified by both positive microscopy and positive culture results.

Previous studies have shown successful treatment of fungi both in vivo and in vitro, using

both methylene blue (MB) and toluidine blue (TB) as the photosensitising agent in PDT

treatment (Kharkwal, et al., 2011). Where possible, if the causative organism can be

successfully identified, this will also be noted for further analysis.

Table 4 – Summary of experimental conditions

Group Toenail Onychomycosis Qualitatively

Present

Treatment

1

POSITIVE MYCOLOGICAL

EXAMINATION:

POSITIVE microscopy i.e. identification

of fungal hyphae under the microscope

and

POSITIVE culture on Sabouraud agar

with chloramphenicol and cycloheximide

confirming the presence of a fungal sp.

PDT repeated on 3 successive days

+ sham daily urea cream and Lamisil spray as

prophylaxis for 3 months

2 Clearanail treatment

(repeated at week 6)

+ daily urea cream and Lamisil spray for 3

months

3 COMBINED TREATMENT:

Clearanail & PDT repeated on 3 successive

days

+ daily urea cream and Lamisil spray for 3

months

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PDT = Photodynamic Therapy using the PACTMED

system and PACT Nail Fungus Gel (toluidine blue based

photosensitiser)

3.2 Initial nail curettage or drilling

Photographs will be taken of all onychomycotic toenails prior to treatment. Patients with

severe toenail onychomycosis (nail dystrophy and hyperkeratosis >2mm thickness) will

undergo nail drilling to reduce the nail down to approximately 2mm thickness. A suitable

tungsten carbide burr will be used to enable quick and effective reduction. Patients

undergoing curettage due to excessive thickness immediately prior to subsequent treatment

will be termed ‘realised’. Patients where severe onychomycosis causes the nail plate to

crumble and disintegrate on curettage will also be termed ‘realised’. Patients with toenail

onychomycosis where the nail plate has remained ≤ 2mm will undergo nail filing with a

diamond deb nail dresser (a new file will be used for each patient to ensure roughening up of

the nail surface), and these patients will be termed ‘unrealised’ within their appropriate

treatment groups.

3.3 Photodynamic therapy (PDT) intervention

The PACTMED

nail fungus therapy (Hahn Medical Systems) LED laser will be used. It

produces a red light (630 nm) and comes shielded, allowing the light source to be accurately

placed 25mm above the nail plate while shielding the user and patient from intense light

exposure. The PS developed by Hahn Medical systems (PACT Nail Fungus Gel) will be

used, which is a toluidine blue based dye (phenothiazinium derivative) with no known or

reported cytotoxicity at the concentrations present in the gel formula. It is assumed that the

gel formula may also contain an ingredient such as EDTA (ethylenediaminetetraacetic acid)

to help with tissue absorption. Only the volunteer and patient will be present at the time of

PDT, and both will be given the appropriate protective eyewear. All fungal infected nails will

be treated, and sufficient time should be scheduled to enable complete treatment, which may

be speeded up by purchasing a second laser unit and treating the nails of the other foot

simultaneously. The PACT Nail Fungus Gel will be applied generously over the affected

nails, ensuring that the entire nail has been covered by gel, and it will be allowed to act for 10

minutes. Within this period, the gel will also be rubbed under the nail fold and nail wall using

an applicator stick to ensure that all exposed affected areas have been covered. Immediately

following this period, the affected nail will be treated with the PACTMED

laser for 9.5 minutes

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(570 seconds) at an approximate distance of 25mm, the shield guard enabling correct

positioning. PDT therapy will be repeated three times on successive days. Following PDT

treatment on the first day, the patient will be also be given CCS 10% urea cream to apply at

night, followed by application of Lamisil spray (an antifungal) in the morning, after complete

drying if the patient has had a shower or bath. This treatment of CCS 10% urea cream and

Lamisil will continue for 12 weeks. The application of CCS 10% urea cream and Lamisil

may help to assist as a prophylaxis preventing re-infection, and will enable test conditions to

be compared against the other treatment groups (Group 2 – Clearanail, and Group 3

combined Clearanail + PDT treatments). The patient will also be offered the opportunity to

bring in all their shoes for decontamination using MesoSilver® antifungal spray, and advised

on best practices to prevent re-infection, such as changing and washing bath mats and

bedding on a hot wash cycle.

3.4 Clearanail therapy intervention

The Clearanail device allows painless and safe drilling of the nail plate, creating 0.4mm

diameter holes (using disposable tips). This device is relatively new to the market, with the

device having been featured in Podiatry Now (Richards, 2015) and with case studies having

been published in March 2015 (Mason, 2015a) and further reports of successful use in the

treatment of onychomycotic nails (Mason, 2015b). To standardise the treatment, the device

will be used to drill holes over the entire surface of the affected nails at approximately 2mm

spacing (see Appendix 1A). A large toenail of width 18mm x length 18mm would require

some 64 holes using this spatial density, whilst a smaller toenail of say 8mm x 8mm would

require only 9. A perforated spatial density template will be created from a plastic nail cover

to ensure standardisation of this spacing. This arrangement will effectively create 1.6mm

bridges between adjacent perforations. A simple calculation of surface area before and after

drilling shows that the top surface area of the nail plate is only reduced by some 2%, and

therefore that the nail plate integrity will remain intact. However, this 2% of ‘opened’ surface

area vastly increases the surface area available within the drilled space itself, analogous to an

open-ended cylinder. PS absorption into the underlying tissue from the drilled pockets may

significantly improve efficacy, allowing the PS dye to penetrate deeper into the surrounding

tissues, the SA having been increased by up to 100%, as illustrated at Appendix 1B. This will

enable improved PS absorption into the nail bed for fungal treatment. Successful case studies

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have been reported using Lamisil spray or gel in this manner on the perforated nail plate

(Mason, 2015a; 2015b), showing improved absorption of the active ingredient into the

underlying tissue. In this study, the device will be used to drill holes into onychomycotic

nails, which will then either be treated with Lamisil spray alone (as in Group 2), or they will

be subjected to PDT PACTMED

therapy as in (Group 3) with the PACT Nail Fungus Gel being

rubbed into the perforations and then subsequently being subjected to daily Lamisil

treatment.

3.5 Combined Treatment – Clearanail and PACTMED+ PACT Nail Fungus Gel

The combined treatment will use both approaches, with predrilling using the Clearanail

device followed by PDT therapy accordingly. Daily Lamisil and urea cream treatment will be

continued for a total of 12 weeks. It is envisaged that this hybrid approach will vastly

improve the efficacy of the absorption of the PS dye and make the PDT treatment more

effective at treating the underlying fungus in the nail plate bed, enhancing outcome.

3.6 Calculation and sample size

The error was established as , in which and are the means of groups 1 and 2.

Assuming both samples are the same size (n1 = n2), the sample size is obtained from the

following equation:

in which and

are the variances in groups 1 and 2, respectively. However, as more than

two groups will be studied, covariate-adjusted analyses were used, by adopting the error

found in the study performed by Figueiredo Souza, et al. (2013), who had initially evaluated

142 patients with clinical signs suggestive of onychomycosis. Of these, 95 satisfied the

inclusion criteria and 80 agreed to participate in and completed the study. This group was

randomly divided into two groups, each with 40 patients. In this proposed study, where the

endpoint is a comparative evaluation of the treatment groups (i.e. clinical cure rate – full,

partial or none), the required sample size has been matched at 40 patients per group, totalling

120 patients over the 3 groups. However, as we expect 5% of data to be randomly missing

from 3 covariates, the sample size has been corrected:

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120 / 0.953 = 140 patients (i.e. 47 patients per group; groups A, B, C)

As each group is further sub-divided into two sets (realised and unrealised), the group size

was increased by 1 to 48 patients per group, making 24 patients per subset, or 144 in total.

Therefore, based on the study by Figueiredo Souza et al. (2013), it was determined that each

group should contain 48 participants. As they originally recruited 144 participants, which had

dropped to 80 by the end of the experiment, a similar extrapolation was made, in that to

achieve 144 ‘completed participants’, an initial recruitment of 259 would be required.

3.7 Outcome Measures

Only participants that have shown positive mycological examination (positive microscopy

and positive culture for fungal identification) will form part of the research, which limits the

treatment groups to those with confirmed onychomycotic fungal toenails. The treatment

groups will be randomly assigned to one of the three groups. The treatment regimen will

formally cease at 12 weeks when daily application of urea cream (night treatment) and

Lamisil spray (day treatment) will cease. Observational evaluations of the nail plate will be

made at the beginning of therapy, and again at weeks 4 and 8 during treatment, and then at

weeks 12, 16, 24 and 48 post treatment, to assess complete, partial or non-clearance of the

original fungal infection. Photographs will also be taken at each stage for subsequent

analysis. Clinical cure (complete clearance) will be defined as the complete replacement of

the mycotic nail bed and dystrophic nail plate with a normal eutrophic nail, allowing for the

mycotic nail to grow out i.e. it is the new nail growth that will be assessed. Microbiological

assessment would be assessed prior to treatment and again at 11 months (48 weeks)

posttreatment.

Patient questionnaires could be developed to assess satisfaction, reduction in discomfort,

reduction in pain, or improved mobility, as a result of treatment.

3.8 Hypothesis

The null hypothesis is that there will be no change in the fungal infection following the use of

either treatment alone, or when combined. The experimental hypothesis is that each method

will produce a reduction in the fungal infection by use of PDT, or Clearanail-Lamisil, or by a

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dual-combined treatment. It is postulated that the best response will be observed from the

dual treatment regimen combining PDT with Clearanail-Lamisil.

3.9 Organisation and statistical analysis of data

The Fisher’s Exact Test will be used to evaluate the correlation between the treatment groups

and time periods. Paired t-tests will be used to compare the data before and after each

treatment to determine whether the various treatments reduce the degree of fungal infection

or provide a clinical cure. Depending on the quality of the digital data collected, more

sophisticated analyses could be performed, rather than a simple assessment of full, partial, or

no clearance. Quantitative analyses of the digital photography, subject to it presenting with a

normal distribution, may allow analysis of variance (ANOVA) followed by a Tukey test to

evaluate differences between each test group and fungal reduction. A Wilcoxon test will also

be used to analyse the data before and after each experiment. A significance level of = 0.05

will be applied.

4. Discussion

The main objective of this proposed study is to evaluate the effect of the PDT (PACTMED

)

system developed by Hahn Medical Systems with the combined used of the Clearanail

device, improving the surface area for absorption of the photosensitising dye (PACT Nail

Fungal Gel) for more effective treatment, enabling enhanced absorption of the PS dye into

the nail plate bed and surrounding tissue. This objective has two aspects: the qualitative and

quantitative evaluation of a clinical cure or reduction in fungal infection. Qualitatively, the

OSI score could be used (Carney et al., 2011), and quantitative analysis of fungal reduction

could be performed using digital software (3D, edge recognition, or other available

quantitative medical imaging technologies). The findings are expected to provide convincing

evidence that PDT is more effective when used in conjunction with the Clearanail device to

achieve a satisfactory clinical cure rate after three simple successive treatments.

4.1 Trial Status

The study would require funding to purchase a Clearanail device and two PACTMED

LED

(630nm) lasers for use within the Podiatry Clinic at the University of Salford, to enable

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research trials to be conducted. Any proposed trials would require consideration and approval

from the Research Ethics Committee at the University of Salford.

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5. References

5.1 Websites

A Simple Solution to A Complex Problem – Clearanail® http://www.Clearanail.com/.

Retrieved from http://www.Clearanail.com/

New product launched to treat fungal nail infections. Edited by Clare Richards

http://issuu.com/redactive/docs/april_15_pn (2015). Podiatry Now- April 2015. Retrieved

from http://issuu.com/redactive/docs/april_15_pn

Terbinafine – United States National Library of Medicine – Liver Tox – Drug Record

Retrieved from http://livertox.nih.gov/Terbinafine.htm

Clearanail proves a hit with podiatrists. Edited by Mason, L. (2015). Clearanail proves a hit

with podiatrists | exceed magazine, Pg 13 October 2015. Retrieved from http://exceed-

magazine.com/review/Clearanail-proves-a-hit-with-podiatrists/

PACT® nail fungus therapy – for effective treatment of nail fungus infections.

Retrieved from http://www.hahnmedicalsystems.com/?page_id=77&lang=en

Cumdente – Photoactivated therapy (Dental concepts - PACT therapy). Retrieved from

https://www.cumdente.com/en/products/pact/pact-therapy.html

Clearanail to help banish fungal nail infections, Edited by Mason, L. (2015). Clearanail to

help banish fungal nail infections | exceed magazine pg 7 March 2015. Retrieved from

http://exceed-magazine.com/review/Clearanail-to-help-banish-fungal-nail-infections/

5.2 Papers

Bahner, J., & Bordeaux, J. (2013). Non-melanoma skin cancers: Photodynamic therapy,

cryotherapy, 5-fluorouracil, imiquimod, diclofenac, or what? Facts and controversies. Clinics

in dermatology. 6(31). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24160289

Brown, S., Brown, E., & Walker, I. (2004). The present and future role of photodynamic

therapy in cancer treatment. The Lancet. Oncology. 8(5). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/15288239

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Carney, C., Tosti, A., Daniel, R., Scher, R., Rich, P., DeCoster, J., & Elewski, B. (2011). A

new classification system for grading the severity of onychomycosis: Onychomycosis

severity index. Archives of dermatology. 11(147). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/22106113

Castano, A., Demidova, T., & Hamblin (2004). Mechanisms in photodynamic therapy: Part

one-photosensitizers, photochemistry and cellular localization. Photodiagnosis and

photodynamic therapy. 4(1). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25048432

Donnelly, R. F., McCarron, P. A., & Tunney, M. M. (2008). Antifungal photodynamic

therapy. Microbiological Research, 163(1), 1–12. doi:10.1016/j.micres.2007.08.001

Drobizhev, M., Gong, A., Meng, F., Rebane, A., Starkey, J. R., & Spangler, C. W. (2006,

February 9). Synthesis, characterization and preclinical studies of two-photon-activated

targeted PDT therapeutic triads. Retrieved from

http://proceedings.spiedigitallibrary.org/proceeding.aspx?articleid=1276071

Elman, M., Slatkine, M., & Harth, Y. (2003). The effective treatment of acne vulgaris by a

high‐intensity, narrow band 405–420 nm light source. Journal of Cosmetic and Laser

Therapy, 5(2), 111–117. doi:10.1080/14764170310001276

Figueiredo Souza, L. W., Souza, S. V. T., & Botelho, A. C. C. (2013). Randomized

controlled trial comparing photodynamic therapy based on methylene blue dye and

fluconazole for toenail onychomycosis. Dermatologic Therapy, 27(1), 43–47.

doi:10.1111/dth.12042

Fleck, C. (2015). Theralase anti-cancer technology presented at international laser

conference. Retrieved from http://www.kereport.com/2015/11/10/theralase-anticancer-

technology-presented-international-laser-conference/

Gupta, A., Jain, H., Lynde, C., Watteel, G., & Summerbell, R. (1997). Prevalence and

epidemiology of unsuspected onychomycosis in patients visiting dermatologists’ offices in

Ontario, Canada--a multicenter survey of 2001 patients. International journal of

dermatology. 10(36). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9372358

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Gursoy, H., Ozcakir-Tomruk, C., Tanalp, J., & Yilmaz, S. (2012). Photodynamic therapy in

dentistry: A literature review. Clinical oral investigations. 4(17). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/23015026

Hamblin, M. R., & Huang, Y.-Y. (2013). Introduction. Retrieved from

http://www.crcnetbase.com/doi/abs/10.1201/b15582-3

Heyes, R. (2015). Photodynamic therapy in the treatment of onychomycosis. Unpublished

manuscript, Salford University.

Kharkwal, G., Sharma, S., Huang, Y., Dai, T., & Hamblin (2011). Photodynamic therapy for

infections: Clinical applications. Lasers in surgery and medicine. 7(43). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/22057503

Konan, Y., Gurny, R., & Allémann, E. (2002). State of the art in the delivery of

photosensitizers for photodynamic therapy. Journal of photochemistry and photobiology. B,

Biology. 2(66). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11897509

Konopka, K., & Goslinski, T. (2007). Photodynamic therapy in dentistry. Journal of dental

research. 8(86). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17652195

Lubeck, D., Bates, M., Fisk, R., Stier, Gause, D., & Schein, J. (2014, April 1).

Onychomycosis. Baseline results of an observational study. Retrieved from

http://www.japmaonline.org/doi/abs/10.7547/87507315-87-11-512

Renno, R. Z., Miller, J. W., Terada, Y., Haddadin, M. J., Michaud, N. A., & Gragoudas, E. S.

(2004, July 1). Selective Photodynamic therapy by targeted Verteporfin delivery to

Experimental Choroidal Neovascularization mediated by a homing peptide to Vascular

endothelial growth factor receptor-2. Retrieved from

http://archopht.jamanetwork.com/article.aspx?articleid=416431

Shafirstein, G., Rigual, N. R., Arshad, H., Cooper, M. T., Bellnier, D. A., Wilding, G.,

Henderson, B. W. (2015). Photodynamic therapy with 3-(1′-hexyloxyethyl)

pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study. Head & Neck.

doi:10.1002/hed.24003

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Souza, L., Souza, S., & Botelho, A. (2014). Endonyx toenail onychomycosis caused by

Trichophyton rubrum: Treatment with photodynamic therapy based on methylene blue dye.

Anais brasileiros de dermatologia., 6(88). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/24474123

Svaasand, L. (1984). Optical dosimetry for direct and interstitial photoradiation therapy of

malignant tumors. Progress in clinical and biological research. Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/6531373

Tardivo, J., Wainwright, M., & Baptista, M. (2015). Small scale trial of photodynamic

treatment of onychomycosis in São Paulo. Journal of photochemistry and photobiology. B,

Biology. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25835504

Valduga, G., Bertoloni, G., Reddi, E., & Jori, G. (1993). Effect of extracellularly generated

singlet oxygen on gram-positive and gram-negative bacteria. Journal of photochemistry and

photobiology. B, Biology. 1(21). Retrieved from

http://www.ncbi.nlm.nih.gov/pubmed/8289115

Wilson, B., Jeeves, W., & Lowe, D. (1985). In vivo and post mortem measurements of the

attenuation spectra of light in mammalian tissues. Photochemistry and photobiology., 2(42).

Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4048297

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6. Attachments

Figure 1: PACTMED

System for fungal toenail treatment

Figure 2: Photochemical mechanisms in PDT

Figure 3: Cell wall structure of fungal cells

Figure 4: Flowchart of study

Appendix 1A & 1B: Clearanail increases the surface area to promote absorption of

the active drug (e.g. Lamisil) or photosensitiser (PACT Nail

Fungus Gel) into the nail bed structure

Appendix 2: Ethical considerations

Appendix 3: Risk analysis

Appendix 4: Scope and limitations

Appendix 5: Further research question

Appendix 6: Table - Pros and cons of PDT therapy

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Figure 1: PACTMED

System for fungal toenail treatment

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Figure 2: Photochemical mechanisms in PDT

Source: http://www.ncbi.nlm.nih.gov/pubmed/22057503 Kharkwal, et al. (2011)

Refer to table 2 for a simplified mode of action

Note: Intersystem crossing – causes a change in the spin of an electron i.e. loss of energy

The ground states PS molecule absorbs light which excites it to the singlet state 1PS

*. This state

can fluoresce or undergo intersystem crossing to lose some energy which allows the PS molecule

to form into a more stable 3PS

* state. It is this

3PS

* state that then loses further energy by reacting

with oxygen molecules naturally present within the tissue (tissue oxygen) to create ROS such as

singlet oxygen (Type II reaction) or superoxide (Type I reaction) i.e. creating activated oxygen

species that are cytotoxic to microbial cells (bacteria, viruses and fungi). Host mammalian cells

can be affected but are more resistant to attack by activated oxygen. Unless the photosensitiser is

destroyed by photobleaching due to oxidation, this cycle can occur many times – causing the

‘oxidative burst’.

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Figure 3: Cell wall structure of fungal cells

‘Free Radical Damage’

A)

B)

Fungal cell wall breached ‘Oxidative Burst’

Adapted from source: http://www.ncbi.nlm.nih.gov/pubmed/22057503 Kharkwal, et al. (2011)

Normal cell wall structure of a fungal cell wall

Fungal cell wall structure – undergoing oxidative attack

Activated oxygen – ROS and singlet oxygen species – result in free radical damage to the

fungal cell wall leading to oxidative crosslinking and fragmentation of proteins, resulting

in cell wall damage and destruction i.e. the oxidative burst.

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Figure 4: Flowchart of study

Adults aged 60 ± 20 years registered at University of Salford Podiatry Clinic

Recruitment n=259, allowing for total drop off of 115 patients

DIAGNOSIS: Visual - dystrophy, hyperkeratosis, discolouration,

subungual debris, onycholysis + Positive Fungal Microscopy

EXCLUDED:

Negative mycological examination ( -ve microscopy / -ve culture )

Those having had recent oral antifungal treatment within the last 6 months / those with nail changes because of skin

diseases or associated systemic disease (see table 3)

INCLUDED:

Positive mycological examination

( +ve culture / +ve microscopy)

GROUP 1:

n = 48 (total size)

n* = 24 (realised)

n* = 24 (unrealised)

GROUP 2:

n = 48 (total size)

n* = 24 (realised)

n* = 24 (unrealised)

GROUP 3:

n = 48 (total size)

n* = 24 (realised)

n* = 24 (unrealised)

Treatment with PDT

PACT-MED & PACT-MED NAIL FUNGUS GEL [PDT]

λ = 630 nm

T = 570 s @ 25 mm distance

Repeated on 3 successive days

Daily night treatment with CCS 10% urea cream and daily day

treatment with Lamisil spray used “prophylactically” for 12 weeks

Treatment CLEARANAIL

Holes drilled over the entire

surface of the nail

Holes re-drilled at week 6 with

further holes added to any new

nail growth

Daily night treatment with CCS 10% urea cream and daily day

treatment with Lamisil spray used for 12 weeks

COMBINED Treatment :

CLEARANAIL & PDT

Holes drilled over the entire

surface of the nail

λ = 630 nm, T = 570 s @ 25 mm

Repeated on 3 successive days

Holes re-drilled or cleared at week

6 with further holes added to any

new nail growth

Daily night treatment with CCS 10% urea cream and daily day

treatment with Lamisil spray used for 12 weeks

Visual measure of outcome at 12 / 24 and 48 weeks (per group) and also split by realised (nail curettage in nails > 2mm thickness i.e. severe OM) vs. non-realised (nail thickness <2mm i.e. less severe OM):

Complete clearance i.e. clinical cure vs. Partial Clearance vs. No change

Analysis of results Qualitative & Quantitative T = time in seconds

*nb: the number of realised vs. unrealised patients

will depend on the randomisation process and may

vary, but total numbers per group should be a

minimum of n=48

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Appendix 1A: Clearanail increases the surface area to promote absorption of the active drug

(e.g. Lamisil) or photosensitiser (PACT Nail Fungus Gel) into the nail bed structure

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Appendix 1B: Clearanail increases the surface area to promote absorption of the active drug

(e.g. Lamisil) or photosensitiser (PACT Nail Fungus Gel) into the nail bed structure

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Appendix 2: Ethical considerations

Informed consent will be obtained, as this is a service generally not offered on the NHS, no

payment for taking part will be arranged. However, travel expenses and the cost of the 10%

CCS Urea Cream and Lamisil spray for continued self-treatment at home will be covered.

Also, appropriate consents will be obtained to take various digital photographs and to be able

to use such photography anonymously in resultant publications.

Also good practice requires that in the opt-in process the patient has been actively involved in

making a conscious decision to take part.

Confidentiality and anonymity will be maintained, with any data or patient files held securely

in locked cabinets.

Potential harm – patients will be fully advised of the schedule of attendance beforehand so

that they do not perceive the number of visits as an inconvenience. The appropriate insurance

and indemnity arrangements will be in place, with the clinician having received prior training

or having had prior experience of use of the PACTMED

system and the Clearanail device.

Patients showing no clinical cure or improvement after 48 weeks, will be offered a further

course of PDT treatment.

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Appendix 3: Risk analysis

Both the PACTMED

PDT system and the Clearanail device are classed as non-invasive

therapies, and the toluidine blue dye as use in the PACT Fungal Nail Gel has no adverse

reports of toxicity at the concentrations that will be used. No adverse risk is expected from

such treatment either alone or combined as proposed in this study.

The participants’ night treatment of 10% CCS urea cream followed by daytime Lamisil spray

treatment for the first 12 weeks is also considered not to pose any significant risk being a

topical application. Should pain or burning or sensitivity occur, the patient will be directed to

stop treatment and attend the clinic for evaluation / or if a severe reaction takes place to seek

immediate emergency medical advice.

Patients will be fully informed and advised of all possible risks.

Safety will be assessed continually through adverse events and laboratory monitoring.

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Appendix 4: Scope and limitations

This study has formed part of a proposal and has a number of limitations namely:

Money – no funds have been sourced or allocated for such proposed study

Equipment – ‘PACTMED

’ and ‘Clearanail’ devices would need to be purchased along

with the necessary consumables.

Pre-trial study – no pre-trial studies has been conducted to assess whether the

‘PACTMED

’ or Clearanail systems are effective for the treatment of onychomycosis.

Non NHS Patients – i.e. university based – requires research ethics committee

approval and also patient numbers may be limited.

Time constraints – the ‘PACTMED

’ device has time issues – approximately 10

minutes per treatment time per nail (two units would speed up treatment times –

especially if treating both feet and all nails).

Measures of outcome – qualitative (OSI score index or other) & quantitative via

digital photographic analyses (edge detection in medical image processing / advanced

eye recognition software). Various medical image processing packages are available.

There should be a correlation between the qualitative and quantitative outcomes.

Toenail growth rates – depending on the health and age of the patient toenail growth

rates could be much slower than expected and there may be variability in toenails

growth rates anyway. Novel techniques could be developed to normalise the growth

rates to correctly quantify eukaryotic nail growth and the clearance of fungus. A

simple technique would involve digitally mapping a marker on the nail – which could

be a glued on marker or perhaps even a hole created by the Clearanail device i.e. as a

reference point.

Qualitative questionnaires – validated / non-validated.

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Appendix 5: Further research question

The PDT regimen could be further modified to ask the following research question:

As tissue oxygen is the source of the oxygen molecules which become ‘activated’ in

PDT, could the PDT treatment regimen be improved by trying to increase the actual

tissue oxygen present prior to PDT treatment. Some research has shown that peroxide

creams can actually increase tissue oxygen in the dermis. Therefore, could a simple

topical pre-PDT treatment using for example a Panoxyl gel (a standard peroxide gel

which comes in 2.5%, 5%, and 10% concentrations) – rubbed into the perforations

created by the CLEARANAIL device - improve subsequent tissue-oxygen levels within

the nail plate and nail bed structures – to further improve the efficacy of the PDT

treatment?

Other Considerations

In the field of podiatry, osteomyelitis and pin-point ulcers on lesser toes may prove

troublesome and difficult to heal. The podiatrist can only really dress the wound and

monitor healing or deterioration, referring on for microbial testing or surgery if

needed. PDT devices are now widely and effectively used in dentistry for the

treatment of infected root canals and periodontitis, etc. It may be that similar fibre

optic PDT systems can be used by podiatrists to treat toe osteomyelitis and leg ulcers

– with equally effective results. Furthermore, PDT therapy can be used in situations

where antibiotic resistance has occurred. Bacteria / fungi and viruses do not possess

the necessary mechanisms that will enable them to become PDT resistant per-se,

making PDT especially suitable in cases where antibiotic resistance has occurred.

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Appendix 6: Table - Pros and cons of PDT therapy

Pros of PDT:

There are no long-term side effects when used properly and in terms of PACTMED

for fungal toenails no side

effect has been reported

Less invasive than surgery (surface treatment can be classed as non-invasive)

The treatment time is usually only short and can often be done as an outpatient or in a normal clinical setting.

With non-invasive PDT therapy – not requiring a sterile or theatre environment under negative pressure

It can be targeted very precisely

PDT can be repeated many times at the same site if needed. PACTMED

for fungal toenails can be repeated

successively if needed

There is often little or no scarring after the site heals. PACTMED

for fungal toenails has no reports of scarring

being an issue

PDT therapy can cost less than other laser treatments (thermolytic lasers) and is often cheaper than other cancer

or antimicrobial treatments

Cons of PDT:

PDT can only treat areas where light can reach. Therefore, it is used to treat problems on or just under the skin,

or in the lining of organs that can be reached with a light source. As light has limited penetration through body

tissues, PDT cannot be used to treat large masses e.g. large tumorous cancers or cancers that have grown deeply

into the skin or other organs. Similarly, PDT therapy is generally not used to treat cancers that have spread to

many places

The drugs used i.e. the photosensitisers used for PDT leave some people very sensitive to light for some time, so

precautions must be taken after the drugs are put in or on the body. In terms of PACTMED

Fungal Nail Gel for

fungal toenails, the toluidine blue staining may leave a blue discolouration for several of days, but will return to

normal in due course and patients would be advised of potential photosensitivity in sunlight and advised to wear

socks covering any treating toenails for several days

PDT can’t be used in people who have certain blood diseases, such as any of the porphyrias (a rare group of

diseases that affect the skin or nervous system) or people who are allergic to porphyrins. This allergy is rare, but

it may happen in those who have had exposure to porphyrins in the past.

Source: http://www.cancer.org/treatment/treatmentsandside/treatmenttypes/photodynamic-therapy