Reflectance Confocal Microscopy to Diagnose Malignant Melanoma and Lentigo Maligna
Conditions: Melanoma (Skin), Lentigo Maligna
Sponsor: Skin Care Network Ltd.

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Reflectance Confocal Microscopy to diagnose malignant 
melanoma and lentigo maligna: HS-MAV-002 
 
 
 
 
 
 
 
 
 
CHIEF INVESTIGATOR:   
 
Howard Stevens, MA (Oxon); MBBS; FRCP, PhD. Consultant Dermatologist,   
 
Address and contact details: 
 
 
 
Skin Care Network 
3 Church Passage 
Wood Street 
Barnet EN5 4QS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date  8-2-17 
 
 
 
 
 
Sponsor:  
 
Medical Advisory Committee (MAC) 
Skin Care Network Barnet Ltd 
3 Church Passage 
Wood Street 
Barnet 
EN5 4QS 
 
 
 
 

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Contents 
Protocol Synopsis .................................................................................................................................. 3 
Study Title: ............................................................................................................................................. 4 
Background ............................................................................................................................................ 4 
Aims ........................................................................................................................................................ 5 
Study Design and Methods .................................................................................................................... 5 
Study Design .................................................................................................................................. 5 
Study Hypothesis ........................................................................................................................... 5 
Setting ............................................................................................................................................ 5 
Participants .................................................................................................................................... 5 
Exclusion criteria ............................................................................................................................ 5 
Informed Consent ............................................................................................................................... 5 
Study Intervention .............................................................................................................................. 6 
Statistics ................................................................................................................................................. 7 
Summary of statistical methods: .................................................................................................... 7 
Sample size calculation .................................................................................................................. 7 
Data management and analysis ............................................................................................................. 8 
Ethical Issues ......................................................................................................................................... 9 
Amendments .................................................................................................................................. 9 
Annual Progress Report ................................................................................................................. 9 
End of study report ......................................................................................................................... 9 
Public disclosure and publication policy ................................................................................................ 9 
Safety Considerations .......................................................................................................................... 10 
Adverse and Serious Adverse Events (SAE) ................................................................................. 10 
Follow-up of adverse events ........................................................................................................ 10 
Data Safety Monitoring Board ...................................................................................................... 10 
Sponsorship & Indemnity ................................................................................................................. 10 
Publication Policy ................................................................................................................................. 11 
Data Safety Monitoring Board .......................................................................................................... 11 
References: .......................................................................................................................................... 11 
Appendix 1: Patient Information Sheet .................................................. Error! Bookmark not defined. 
Appendix 2: Patient Consent Form ........................................................ Error! Bookmark not defined. 
 
 
 

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Protocol Synopsis 
Protocol ID 
Version 0.4. 8
th February 2017 
Protocol Title 
HS-MAV-002 
Development phase 
II 
Primary endpoint 
Specificity & Sensitivity of RCM in diagnosing adult MM 
and LM compared to standard histology  
Secondary endpoint 
Inter- & intra-observer agreement in assessing RCM 
images. 
Time taken for in-vivo examination of lesion. 
Study design 
This is an observational, non-randomised, non-
controlled, prospective cohort study to look at the 
efficacy of in vivo RCM as a diagnostic tool in the 
diagnosis of MM and LM. 
 
Key Inclusion Criteria 
Patients 18 years or older with a suspected diagnosis of 
MM or LM  
Key Exclusion Criteria 
Recurrent MM or LM  
Patient on immunosuppresants 
Patient with significant co-morbidity or skin disease 
Patient not suitable for diagnostic biopsy 
Location of lesion unsuitable, inaccessible or impractical 
for scanning with RCM as determined by investigator 
Patient Accrual 
Up to 700 Patients over 18 months 
Protocol follow-up procedure 
None 
Chief Investigator 
Dr Howard Stevens 
Co-Investigators 
Prof Giovanni Pellacani, University of Modena 
Other key staff 
Dr Ioulios Palamaras Dermatologist 
Host Institution 
Skin Care Network Barnet 
Funding 
None 
 
 

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Study Title: 
Reflectance 
Confocal 
Microscopy 
to 
diagnose 
adult 
malignant melanoma and lentigo maligna: HS-MAV-002 
Background 
Pigmented lesions suspicious for Malignant Melanoma (MM), Spitz naevi, Spitzoid melanoma or 
Lentigo Maligna (LM) can be challenging to diagnose. Both visual and dermatoscopic diagnostic 
performance of clinicians is highly variable and highly dependent on clinician training, and the 
number of lesions needed to excise to find one cancerous lesion (NNE) can be 14 or higher [1]. 
 
Reflectance confocal microscopy (RCM) is a high resolution, non-invasive method for visualising skin 
in cellular detail in-vivo, and has been shown to be diagnostic for MM and LM in adult populations. 
Meta-analysis has shown a per lesion sensitivity of 93% [95% CI 89–96] and a specificity of 76% 
[95% CI 68–83] for MM in equivocal lesions [2].  
 
Current guidelines assume that only dermatoscopically equivocal lesions are examined using RCM, 
and that the potential for RCM to impact sensitivity is therefore very limited [3]. However, RCM can 
significantly help with equivocal lesions, with a sensitivity of 100% and a specificity of 69%, avoiding 
35 of the 51 nevi in one study [4]. A recent paper showed the number needed to excise (NNE) 
reduced from 14.6 to 6.8 with the addition of RCM [1]. 
 
At the Royal Free Hospital they currently surgically excise approximately 100 MM and LM each year. 
Because of the dangerous nature of the disease, it is very important that no MM lesions are missed. 
This leads to a requirement to biopsy a large number of benign lesions to ensure that sensitivity is 
maintained at as close to 100% as possible. The NNE measure describes this, detailing the number 
of lesions excised in order to find one malignant lesion. 
 
Recently, NICE guidance (Nov 2015) was issued regarding the use of RCM in the management of 
skin cancer [5]. They concluded the following: 
 
“The VivaScope 1500 and 3000 imaging systems show promise but there is currently 
insufficient evidence to recommend their routine adoption in the NHS…” 
 
“Further 
research…on 
using 
the 
VivaScope 1500 and 3000 
imaging 
systems 
is 
recommended in the following areas: 
 
…the impact on clinical workflows for melanoma and basal cell carcinoma 
assessment in secondary care settings. 
 
…the number of confirmatory diagnostic biopsies needed for people with a clinical 
diagnosis of melanoma before definitive treatment is started.” 
 
Both instruments are available for this study, and either / both will be used depending on anatomic 
considerations. This would be the first study in the UK assess the use of reflectance confocal 
microscopy in the diagnosis of MM and LM. If RCM is able to accurately diagnose melanoma in a 
significantly higher proportion of patients then Number of benign lesions Needed to Excise (NNE) to 
find a MM or LM might reasonably be reduced by 30% from its current value of approximately 10. 

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Aims  
 
We propose to undertake a study to determine the diagnostic utility of using the RCM for the 
diagnosis of adult Malignant Melanoma (MM), Spitz naevi, Spitzoid melanoma and Lentigo Maligna 
(LM) in a tertiary referral centre as outlined by the recent NICE report (Nov 2015). 
Study Design and Methods 
Study Design 
This is an observational, non-randomised, non-controlled, prospective cohort study to look at the 
efficacy of in vivo RCM as a diagnostic tool in the diagnosis of MM and LM. 
Study Endpoints 
The hypothesis of this study is that the use of RCM is would reduce the NNE prior to definitive 
treatment by at least 30% from the current value of approximately 10. 
 
The secondary hypothesis is that the intra- & inter-observer agreement for interpreting the RCM 
images will have  kappa scores 0.6 or greater (indicating good agreement). 
Setting and recruitment 
Patients will be recruited from the outpatient clinics of the Skin Care Network Barnet. 
Participants 
The number of true negative lesions examined in this study will be 654. It is anticipated that this will 
result in a total of 661 lesions being recruited. 10% of participants are expected to have more than 
one lesion sampled. 
 
The result of biopsy for each lesion will not be known until after the lesion has been included in the 
study. Therefore lesions will be added to the study until the required number of true negatives has 
been included. 
 
Recruits must fit the following criteria: 
 
1. Age 18 years or older 
2. Patient with a pigmented lesion recommended for excision because of suspicion of MM or 
LM.  
3. Patient willing and able to give informed consent 
Exclusion criteria 
1. Recurrent MM or LM 
2. Patient on immunosuppresants 
3. Patient with significant co-morbidity or skin disease 
4. Patient not suitable for diagnostic biopsy 
5. Location of lesion unsuitable, inaccessible or impractical for scanning with RCM as 
determined by investigator 
Informed Consent  
The Investigator, or an authorised member of their team, will obtain written informed consent for 
patients. It is anticipated that patients will be approached regarding participation after diagnosis 
when they have been identified as having an equivocal pigmented lesion requiring biopsy under 
standard of care.  

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When obtaining informed consent, investigators must ensure that they adequately explain the aim, 
anticipated benefits and potential hazards of taking part in the trial to the patient. Investigators 
should also stress that patients are free to refuse to take part or withdraw from the trial at any time. 
The patient should be given ample time to read the appropriate patient information sheet and to 
discuss their participation with others if requested. The patient must be given an opportunity to ask 
questions which should be answered to their satisfaction. The right of the patient to refuse to 
participate in the trial without giving a reason must be respected.  
 
Patients who agree to take part should be asked to sign and date the latest version of the consent 
form. The Investigator, or an authorised member of their team, must then sign and date the form. A 
copy of the consent form should be given to the patient, a copy should be filed in the clinical notes, 
and the original placed in the site file. 
Study Intervention 
Patients will be assessed in clinic by a consultant dermatologist. Patients with an equivocal 
pigmented lesion will be invited to participate. Clinical and dermoscopic images will be taken by the 
team as part of their routine standard of care. Patients will be invited to participate in the trial and 
provided with a patient information leaflet. They will be given sufficient time to review the information 
sheet and ask questions.  
 
Patients will be consented to having confocal microscopy performed of the target lesion before 
undergoing biopsy for histology. Acceptable biopsy methods will include punch, shave or excision 
biopsy with the intention of providing a diagnosis. These patients would be having photographs, 
including dermoscopic images, and a biopsy as part of their standard of care, therefore the only 
additional intervention is examination with the confocal microscope.   
 
Confocal microscopy will be performed by a trained clinician, either a doctor or nurse specialist. 
Once the operator is satisfied that all images (clinical, dermoscopic and confocal) have been taken to 
a standard that will allow independent assessors to provide a diagnosis, they will be stored on a 
secure server and indexed anonymously with reference to the subject’s assigned unique trial 
number. Imaging time is expected to last approximately 15-20 mins per patient. In this way, data will 
be anonymised to allow blinding of the diagnosis with reference to the images during the analysis 
phase. The trial co-ordinator will be responsible for maintaining the database containing the patient 
and lesion information in addition to the images. The co-ordinator will be the only unblinded member 
of the investigatory team. 
 
The images taken of the tumour by the confocal microscope system will be anonymised. Imaging will 
include clinical imaging on an area of 30x30 to 50x50 cm2, centred around the lesion of concern, a 
close up image of the lesion, and the high-resolution picture of the lesion. The clinical picture will be 
masked appropriately to preserve patient anonymity. 
 
These images will then be examined by a different dermatologist who has undergone training in 
examining confocal images. The images will also be sent to a dermatologist in Modena who is an 
expert in interpreting confocal microscopic images – both of these dermatologists will be blinded as 
to the patient’s history and the results of the diagnostic biopsy except age, sex and relevant 
information concerning lesion history and changes. The clinicians interpreting the confocal 
microscope images will be asked to complete the following questions: 
 
1. RCM description: features of MM / LM.  
2. RCM diagnosis: MM / LM (Y/N); degree of certainty (0=low; 1=possible; 2=almost certain) 
3. RCM quality of imaging: 0=low/don’t feel confident; 1=acceptable/could be improved; 
2=high quality (free text for images scoring 0) 
 
The biopsies will undergo routine processing in our histopathology laboratory as normal and will be 
analysed by a pathologist who will be unaware of the findings on confocal microscopy. 

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Statistics 
Summary of statistical methods: 
The primary hypothesis of this study is that the use of RCM is would reduce the number needed to 
excise (NNE) prior to definitive treatment by at least 30% from the current value of approximately 10. 
The secondary hypothesis is that the intra- & inter-observer agreement for interpreting the RCM 
images will have kappa scores 0.6 or greater (indicating good agreement). 
 
The 95% confidence interval for the specificity and sensitivity will be calculated for both observers.  
The NNE will also be reported along with a 95% confidence interval. 
 
To assess the inter-observer agreement the Kappa statistic will be reported alongside the proportion 
of agreements and disagreements. 
 
Sample size calculation 
The sample size has been determined in terms of the number of lesions examined, and assumes that 
lesions within a patient are independent.     
 
Table 1 shows the relationship between the NNE and the specificity, assuming 100% sensitivity, for 
two values of the percentage positive in the population.  For example if there are 5% positive lesions 
in the population of equivocal lesions and if NNE is to be 6, the specificity must be 74%.   If the 
proportion of positive lesions is lower (2%) then a higher specificity is required to achieve each NNE 
value.  
 
Table 1:  Specificity as a function of NNE and N/P 
% true P
N/P
NNE
Specificity
2%
49
6
90%
2%
49
7
88%
2%
49
8
86%
2%
49
10
82%
2%
49
15
71%
5%
19
6
74%
5%
19
7
68%
5%
19
8
63%
5%
19
10
53%
5%
19
15
26%
 
 
The numbers of lesions required to provide a lower confidence limit for the specificity which is no 
more than 3% lower than the estimate of specificity have been calculated for NNE values of 6, 7 and 
8, for 5% and 2% true positives in the population, based on Table 1.  Table 2 shows the results.  
Table 2:  Numbers of true positive and true negative lesions required for protocol HS-MAV-002 

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NNE 
True positives: 
 
6 
7 
8 
5% 
Specificity 
75% 
68% 
63% 
 
True negative lesions 
required 
564 
654 
701 
2% 
Specificity 
90% 
88% 
86% 
 
True negative lesions 
required 
271 
317 
362 
 
The number of true negative lesions examined in this study will be 654. Therefore at anticipated 
prevalence, total number of lesions recruited to the study should be less than 700. 
 
The result of biopsy for each lesion will not be known until after the lesion has been included in the 
study.  Therefore lesions will be added to the study until the required number of true negatives has 
been included.  The resulting true positives will be used to estimate the sensitivity as a secondary 
endpoint. 
  
Data management and analysis  
The Clinical Record Forms (CRFs) must be completed, signed and dated by the Investigator or an 
authorised member of staff prospectively. The completed originals will be collected by the trials co-
ordinator and held in the site file as source documents. It is the responsibility of the Investigator to 
ensure that CRFs have been completed correctly and that the data are accurate. Entries should be 
made in ballpoint pen and should be legible. Any errors should be crossed out with a single stroke, 
the correction inserted and the change initialled and dated. All missing and ambiguous data will be 
queried.  The CRF may be amended as appropriate; this will not constitute a protocol amendment. 
The revised CRF should be used by all participating sites with immediate effect.  
 
The data will be transferred anonymously to a password –secured electronic database. All patients 
will be pseudo-anonymised. Data will be stored in databases at Skin Care Network, and any copies 
to be taken off site (for example for statistical analysis or for analysis by the equipment provider) will 
be anonymised and will be protected by encryption and password. Access will be restricted to 
medical and research personnel, and appropriate support personnel. Specific trial information will be 
restricted to Investigators and collaborators. The trial co-ordinator will be responsible for the daily 
administration of the database.  
 
An initial interim analysis of the data will be planned after 25 patients to ensure the RCM images are 
of sufficient quality to continue and complete the study. Data validation will be co-ordinated under 
the supervision of the trial statistician once the recruitment target has been reached. The final 
analysis and publication of results will be undertaken after all patients have been recruited. The 
accrual period is estimated to be 12 months but will be continued until sufficient numbers are 
obtained for the study to reach significance. Once the dataset is complete, assessment of the RCM 
images by the blinded investigators will take place to allow statistical analysis of the primary and 
secondary endpoints, namely specificity, sensitivity and kappa statistics. Analysis of the final dataset 
is expected to take place within 6 months of completion of accrual.  Publication is expected within 
12 months of completing the trial. 

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Ethical Issues 
The study proposal is subject to approval by the appropriate Ethics Committee and the host 
organisation’s Medical Advisory Committee (MAC), and will adhere to Good Clinical Practice 
Guidelines. The study will be conducted according to the principles of the Declaration of Helsinki and 
in accordance with the Medical research Involving Human Subjects Act (WMO). 
Amendments 
Amendments are changes made to the research after a favourable opinion by the accredited Ethics 
Committees has been given. All amendments will be notified to the Ethics Committees that gave a 
favourable opinion.  
 
A ‘substantial amendment’ is defined as an amendment to the terms of the Ethics Committee(s) 
application, or to the protocol or any other supporting documentation, that is likely to affect to a 
significant degree: 
 
• 
the safety or physical or mental integrity of the subjects of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the Ethics Committees and to the competent authority.  
 
Non-substantial amendments will not be notified to the accredited Ethics Committees and the 
competent authority, but will be recorded and filed by the sponsor.  
 
Annual Progress Report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited Ethics 
Committee once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
End of study report 
The investigator will notify the accredited Ethics Committees and the competent authority of the end 
of the study within a period of 8 weeks. The end of the study is defined as the last patient’s last 
follow-up after 1 year.  
 
In case the study is ended prematurely, the investigator will notify the accredited Ethics Committees, 
including the reasons for the premature termination. Within one year after the end of the study, the 
investigator/sponsor will submit a final study report with the results of the study, including any 
publications/abstracts of the study, to the accredited Ethics Committees and the Competent 
Authority. 
Public disclosure and publication policy 
The study documentation must be retained at all times in a secure and protected environment. This 
will ensure the integrity of the study data is maintained and protects patient confidentiality.   
 
The CCMO (Central Committee on research involving Human subjects) statement according 
publication policy is obligatory for participants of the HS-MAV-002 Study and the study sponsor. The 
results of scientific research involving human subjects must be disclosed unreservedly. For the 

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avoidance of doubt, negative study results will be published. Further information on publication is 
outlined in the clinical trial agreement.  
 
Registration of the HS-MAV-002 study will be completed following successful ethical approval. 
Safety Considerations 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and 
the reviewing accredited Ethical Committees if anything occurs, on the basis of which it appears that 
the disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited Ethics Committees, 
except insofar as suspension would jeopardise the subjects’ health. The investigator will take care 
that all subjects are kept informed. 
Adverse and Serious Adverse Events (SAE) 
The investigator must inform the Sponsor, within one working day by telephone or fax, of any 
serious adverse event. The investigator must also complete and forward a serious adverse event 
form within four calendar days to the MAC of Skin Care Network. The investigator will be asked to 
assess the serious adverse events causal relationship to the study device. All SAEs will be reported 
for up to 30 days post-biopsy and RCM scanning 
 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the experimental treatment. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
A serious adverse event is any untoward medical occurrence that:  
 
§ 
results in death; 
§ 
is life threatening (at the time of the event); 
§ 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
§ 
results in persistent or significant disability or incapacity; 
§ 
is a congenital anomaly or birth defect; 
§ 
is a new event of the trial likely to affect the safety of the subjects, such as an 
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the 
treatment of a life threatening disease, major safety finding from a newly completed 
animal study, etc. 
 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first knowledge of the 
adverse reaction. This is for a preliminary report with another 8 days for completion of the report.  
Follow-up of adverse events 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
Data Safety Monitoring Board 
Not applicable to this study 
Sponsorship & Indemnity 
This trial is sponsored by Skin Care Network Barnet Ltd. The trial is being coordinated by Skin Care 
Network. These offices do not hold insurance against claims for compensation for injury caused by 
participation in a clinical trial and they cannot offer any indemnity. There are no specific 
arrangements for compensation made in respect of any serious adverse events occurring though 
participation in the study, whether from listed side effects, or others yet unforeseen. Skin Care 

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Network has a duty of care to patients receiving treatment, whether or not the patient is taking part 
in a clinical trial. Compensation is only available via Clinic and consultant medical indemnity policies 
and only in the event of proven clinical negligence.  
Publication Policy 
All presentations and publications, including abstracts, relating to or arising from, the trial must be 
authorised by the Trial Medical Advisory Committee and the Chief Investigator. 
 
Serious adverse events (SAE) 
 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first knowledge of the 
adverse reaction. This is for a preliminary report with another 8 days for completion of the report.  
 
Follow-up of adverse events 
 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
Data Safety Monitoring Board 
Not applicable to this study 
 
References: 
1. Pellacani, G., et al. (2014) "Reflectance confocal microscopy as a second-level examination in skin 
oncology improves diagnostic accuracy and saves unnecessary excisions: a longitudinal 
prospective study" British Journal of Dermatology, 171(5), pp. 1044-51. 
2. Stevenson, A., et al. (2013)  "Systematic review of diagnostic accuracy of reflectance confocal 
microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. 
Dermatol Pract Conc. 2013; 3 (4): 5."  
3. Scope, A. & Longo, C. (2014) "Recognizing the benefits and pitfalls of reflectance confocal 
microscopy in melanoma diagnosis" Dermatology practical & conceptual, 4(3), pp. 67. 
4. Lovatto, L., et al. (2015) "In vivo reflectance confocal microscopy of equivocal melanocytic lesions 
detected by digital dermoscopy follow-up" Journal of the European Academy of Dermatology 
and Venereology, 29(10), pp. 1918-25. 
5. NICE (2015)  "VivaScope 1500 and 3000 imaging systems for detecting skin cancer lesions,"  NICE, 
NICE Diagnostic Guidance [DG19].