Microwave Therapy for Treatment of Precancerous Actinic Keratoses

Study Overview
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Brief Summary
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This is a two-stage feasibility study to determine if focussed microwave energy is a suitable treatment for Actinic Keratoses (AK). The two study stages are as follows: Stage 1: To determine the electrical properties of permittivity in AK on the hand and bald scalp for subsequent optimisation of the SWIFT instrument to provide the correct dose of microwave energy to the AK. Stage 2: Evaluate the efficacy of microwave energy as a treatment for AK Evaluate the long-term resolution of AK following microwave treatment Assess the feasibility and acceptability of using microwave energy as a treatment for AK Identify the potential mode of action of microwave energy in the treatment of AK. The primary objective is to evaluate the efficacy of microwave therapy versus no treatment on the resolution of AK lesions using visual assessment. The primary outcome measure is full or partial resolution of the AK assessed by skin examination.

Detailed Description
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This study is a collaboration between the University of Dundee, NHS Tayside and Emblation Ltd, funded by Innovate UK. Emblation is a Scottish based Small Medium sized Enterprise (SME) and is an established global leader in the design, development and manufacture of microwave medical devices. Actinic keratoses (AK) are believed the most common pre-cancerous lesions in humans and are precursors to invasive cutaneous squamous cell carcinoma (cSCC), a malignancy that has more than doubled in incidence in the UK in the last decade due to ageing populations and increased UV exposure (Goon 2017). The UK incidence of cSCC now exceeds 30,000 annually (estimated >50,000 cases/year, Public Health England, unpublished data) with significant health burden and NHS costs These skin cancers are often multiple, especially in immunosuppressed high-risk populations. AK are very common sun damage skin lesions found on sun-exposed areas of the skin, such as the backs of hands and bald scalp. Up to 70% of our elderly population have AK and 65% of cSCC arise from previously identified AK. AK are readily identified clinically so AK treatment offers an important opportunity for cancer prevention, but our ability to treat is limited by undesirable local adverse reactions from existing topical treatments which fail to balance effectiveness, side effects and cost. None of the currently available treatments for AK are suitable for widespread use in the community and are only partially effective. Other more effective treatments such as photodynamic therapy are expensive and time consuming and need to be delivered by experts in secondary care. NHS dermatologists are already overburdened and elderly patients with AK do not wish to travel. AK therapy would be greatly improved by a cheap, convenient, well-tolerated and efficacious therapy that can be delivered closer to home by General Practitioners (GPs) or nurses. Clinically, AK display a spectrum of severity from mild Grade 1 lesions, which are just visible and just (barely) palpable, through Grade 2 red and scaly lesions (easily felt and seen), to the most severe Grade 3 lesions, which are grossly hyperkeratotic and thickened skin lesions. In practice, it is easier to grade them as 'thin' (just palpable) or 'thick' (with substance to them). It is possible that the dielectric properties of Thick and Thin AK will differ and therefore the measurement study will need to be carried out on both types of AK such that the appropriate microwave dose can be given to these variable skin lesions The investigator's hypothesis is that localised microwave energy therapy is a suitable treatment for Actinic Keratosis (AK) skin lesions. The use of microwave technology is well established as ablative doses for treatment of malignancy e.g. hepatocellular carcinoma. There are no known studies using microwave for treatment of pre-cancerous skin conditions or skin cancers. Furthermore, there is very little understanding of the biological process evoked by localised microwave exposure in the skin or of the clinically-relevant biological mechanisms triggered. Emblation already have a CE-marked microwave instrument used successfully for the treatment of plantar viral warts, the SWIFT device. The investigators now wish to undertake a feasibility trial in 12 participants, each with multiple AK on dorsal hand skin or bald scalp or both. The trial will examine the tolerability, acceptability, efficacy and long-term resolution of AK following one or more treatments with microwave energy delivered using the SWIFT device. Previous studies performed by Emblation using SWIFT on plantar viral warts found it to be effective and safe. Some participants experienced minor discomfort during the microwave therapy but any pain stopped when treatment stopped. Some reddening of the skin at the treatment site may occur but this resolved after 24 hours. Some instances of a haematoma have been seen at larger doses, typically resolving within 7 days. This will be a two-stage study, stage 1 to measure the electrical properties of AKs in patients. The data from stage 1 allows derivation of the power settings to be used with SWIFT for AK in stage 2, to conduct a randomised controlled trial of microwave treatment, delivered using SWIFT, versus no treatment. The SWIFT device has variable power and duration controls, the protocol suitable for plantar viral warts is unlikely to be compatible with AK. Plantar warts (verrucas) are considerably thicker than AK and are located on much thicker, more robust areas of normal skin. AK are most common in the elderly population and are located on thinner, more delicate skin. The investigators therefore anticipate that AK will require a smaller dose of microwave energy than plantar warts. In order to derive the correct power and duration settings for the Swift instrument and impart the correct amount of electromagnetic energy (referred to as dose) into the AK, the dielectric properties of AK need to be determined to confirm how the specific tissue responds to the electromagnetic energy (microwave). By measuring relative permittivity (commonly abbreviated to Epsilon relative Er) the dielectric properties of the AK can be determined. The established method of measurement requires the tissue/material under test to come into contact with a specially designed probe attached to an instrument that measures the response to a radiated signal at the same frequency (8GHz) as that used in Emblation's product Swift. There are a number of instrument and probe manufacturers e.g. Keysight (HP/Agilent), SPEAG, Anritsu. The probe can be used to test solids, liquids and biological tissues by placing the probe in direct contact for a few seconds whilst remaining still during data acquisition by the instrument. The instrument (Anritsu MS46122A) providing the probe excitation conforms to the following standards: CE Mark, Low voltage (2006/95/EC) and Safety (EN 61010-1:2010). The energy imparted into the lesion for the measurement will not exceed 0.5mW, by way of comparison this is far less than a mobile phone (up to 500mW) and a FitBit (1.6mW) thus there is no inherent danger to the volunteer. Emblation employees will operate the instruments and direct the subjects to the probe. Other study team staff may work in conjunction with NHS staff at the time of recruitment and/or at the time of measurement. Microwave energy is converted to heat in the skin layers and forms the basis of the therapy. The target temperature of 43-46 degrees Centigrade is crucial in eliciting the correct immune response in the tissue. As the current instrument is 'tuned' with an antenna for plantar warts, it may not be as efficient at imparting the energy into the AK lesions and the target temperature may not be achieved with the same power and duration settings. Conversely, if the AK provides a more efficient conversion of microwave to temperature, potentially too high a temperature may be reached at a given power and duration combination. Stage 1 data will be analysed to model the efficiency of the current antenna in computer simulations and values for input power (W) and duration (s) will be derived from the modelling data, subsequently to be used in the stage 2 of the trial. This will provide the correct dose of microwave energy to be used in Stage 2. Once the settings required for AK have been determined, participants will be recruited into Stage 2 in order to determine efficacy, long term resolution, tolerability and potential mode of action of microwave treatment for AK.

Official Title
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Microwave Therapy for Treatment of Precancerous Actinic Keratoses

Conditions
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Actinic Keratoses, Precancerous Skin Lesion

Intervention / Treatment
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* Other: Microwave treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants Age 18 years and over Clinical diagnosis of precancerous Actinic Keratosis made by a dermatologist Able to perform study assessments Exclusion Criteria: Inability to give informed consent Implantable Cardioverter-defibrillator (ICD), pacemaker or other implantable device Metal implants at site of treatment Known allergy or intolerance to microwave therapy Unstable co-morbidities (cardiovascular disease, active malignancy, vasculopathy, inflammatory arthritis) which, in the opinion of the Chief Investigator (CI), would make the patient unsuitable to be enrolled in the study. Individuals who are immunosuppressed (organ transplant recipients, haematologic malignancies, HIV). Individuals will not be enrolled to the study if they are participating in the clinical phase of another interventional trial or have done so within the last 30 days. Individuals who are participating in the follow-up phase of another interventional trial, or who are enrolled in an observational study, will be co-enrolled where the CIs of each study agree that it is appropriate.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, internally controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Microwave energy treatment<br>The microwave treatment will be delivered using the microwave instrument, SWIFT, manufactured by Emblation and CE marked for this indication, will be used to deliver the microwave treatment. The microwave dose will be between 2 Watt and 4 Watt. The treatment will consist of 3, 2 to 3 second bursts delivered to the same lesion with 5-20 seconds between bursts. | Other: Microwave treatment<br>* Microwave energy delivered using the microwave instrument, SWIFT, manufactured by Emblation and CE marked for dermatology applications.<br>|
| No Intervention: Control<br>No treatment will be given. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of AK Lesions Following Microwave Treatment | The resolution of each treated AK lesion will be determined by clinical assessment. Resolution is predetermined as either partial (resolution of the area covered by the microwave probe, but with a rim or persistent AK) or full (complete resolution of the entire AK) over all time periods. Response will be assessed at visits 3 (day 8), 4 (day 15), 6 (day 28), 8 (day 42), 10 (day 60) and 11 (day 120). Mixed-effects logistic regression models analysed the effect of microwave therapy with random effects for participant and visit (≤ 6 per participant). Each visit will be analysed as a categorical variable as they were spaced unequally in time. Variables representing sex, age, skin site (hand/scalp) and AK subtype (thick/thin) will be included as covariates. The data reported in the outcome table is the number of resolved AK lesions. | Baseline, day 8, 15, 28, 42, 60 and 120 | 
| Complete Resolution of AKs Following Microwave Treatment | The resolution of each treated AK lesion will be determined by clinical assessment. Resolution is predetermined as either partial (resolution of the area covered by the microwave probe, but with a rim or persistent AK) or full (complete resolution of the entire AK) over all time periods. Treatment will be given at day 1, with a second treatment on day 28 based on a clinical decision. Response will be assessed at visits 3 (day 8), 4 (day 15), 6 (day 28), 8 (day 42), 10 (day 60) and 11 (day 120). Clinical photos will be taken at each hospital visit. Mixed-effects logistic regression models analysed the effect of microwave therapy with random effects for participant and visit (≤ 6 per participant). Each visit will be analysed as a categorical variable as they were spaced unequally in time. Variables representing sex, age, skin site (hand/scalp) and AK subtype (thick/thin) will be included as covariates. | Baseline, day 8, 15, 28, 42, 60 and 120 | 
| Partial Resolution of AKs Following Microwave Treatment | The resolution of each treated AK lesion will be determined by clinical assessment. Resolution is predetermined as either partial (resolution of the area covered by the microwave probe, but with a rim or persistent AK) or full (complete resolution of the entire AK) over all time periods. Treatment will be given at day 1, with a second treatment on day 28 based on a clinical decision. Response will be assessed at visits 3 (day 8), 4 (day 15), 6 (day 28), 8 (day 42), 10 (day 60) and 11 (day 120). Clinical photos will be taken at each hospital visit. Mixed-effects logistic regression models analysed the effect of microwave therapy with random effects for participant and visit (≤ 6 per participant). Each visit will be analysed as a categorical variable as they were spaced unequally in time. Variables representing sex, age, skin site (hand/scalp) and AK subtype (thick/thin) will be included as covariates. | Baseline, day 8, 15, 28, 42, 60 and 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Pain Experienced During Treatment | To evaluate the safety and tolerability of microwave treatment as a therapy for AK, participants were asked about level of pain during treatment. Participants were asked to rate their pain level during each treatment as i) mild, ii) moderate or iii) severe. | Treatment 1 (day 1) and treatment 2 (day 28) | 
| Duration of Pain Post Treatment | To evaluate the safety and tolerability of microwave treatment as a therapy for AK, participants were asked about the duration of pain immediately after each treatment. Duration was grouped into 5 pre-determined periods, i) few seconds, ii) up to 5 minutes, iii) up to 10 minutes, iv) up to 20 minutes and v) over 30 minutes. The decision to administer a second treatment was made by the investigator. | Treatment 1 (day 1) and Treatment 2 (day 28) | 
| Change in Ki67 Staining Determined Immunohistochemically by the Use of Specific Antibodies on Fixed Material | To identify the mode of action of microwave treatment on biomarkers of cell proliferation as a therapy for AK. Results are provided on the staining positivity scale of +, ++ and +++. The minimum value is + , meaning the least staining. The maximum value is +++, meaning the most staining identified. | Day 15 | 
| Change in Hematoxylin and Eosin Stain | To identify the mode of action of microwave treatment on biomarkers of cell survival. | Day 15 OR day 42 |