Reflectance Confocal Microscopy to Diagnose Basal Cell Carcinoma
Conditions: Basal Cell Carcinoma
Sponsor: Skin Care Network Ltd.

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Reflectance Confocal Microscopy (RCM) to diagnose basal 
cell carcinoma: HS-MAV-003 
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:  
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 ............................................................................................................. 7 
Ethical Issues ......................................................................................................................................... 8 
Amendments .................................................................................................................................. 8 
Annual Progress Report ................................................................................................................. 8 
End of study report ......................................................................................................................... 8 
Public disclosure and publication policy ................................................................................................ 8 
Safety Considerations ............................................................................................................................ 9 
Adverse and Serious Adverse Events (SAE) ................................................................................... 9 
Follow-up of adverse events .......................................................................................................... 9 
Data Safety Monitoring Board ........................................................................................................ 9 
Sponsorship & Indemnity ................................................................................................................... 9 
Publication Policy ................................................................................................................................. 10 
Data Safety Monitoring Board .......................................................................................................... 10 
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 0.5, 14th February 2017 
Protocol Title 
HS-MAV-003 
Development phase 
II 
Primary endpoint 
Specificity & Sensitivity of RCM in diagnosing Basal Cell
Carcinoma in non-pigmented lesions compared to 
standard histology  
Secondary endpoint 
Inter- & intra-observer agreement in assessing
RCM images 
Study design 
This 
is 
a 
non-randomised, 
non-controlled,
prospective observational study to look at the
efficacy of in vivo RCM as a diagnostic tool in the
diagnosis of BCC. 
Key Inclusion Criteria 
Patients 18 years or older with a suspected 
diagnosis of BCC 
Key Exclusion Criteria 
Recurrent or otherwise high-risk BCC 
Patient with basal cell naevus syndrome 
Patient treated with hedgehog inhibitor medication 
(vismodegib) 
Patient not suitable for diagnostic biopsy 
Location of lesion unsuitable, inaccessible or
impractical for scanning with RCM as determined
by investigator 
Patient Accrual 
328 patients over 18 months 
Protocol follow-up procedure 
None 
Chief Investigator 
Dr Howard Stevens 
Co-Investigators 
Dr Martina Ulrich, Dermatologie am Regierungsviertel 
Berlin. 
Other key staff 
Dr Ioulios Palamaras Consultant Dermatologist 
Host Institution 
Skin Care Network Barnet  
 
Funding 
None 
 
 

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Study Title: 
Reflectance Confocal Microscopy (RCM) to diagnose basal 
cell carcinoma: HS-MAV-003 
Background 
Basal cell carcinoma (BCC) is the commonest skin cancer in the UK and its incidence is rising year 
on year. Extrapolation of data from the East Norfolk and Waveney area of the UK suggests 
approximately 200 000 patients had 247 000 BCCs treated surgically that in 2010 (this estimate does 
not include those treated by other means such as cryotherapy, topical chemotherapy, photodynamic 
therapy or radiotherapy, without histology) [1]. 
 
There are many treatments for BCC depending on the subtype. Thin or superficial BCCs (sBCC) can 
be treated with topical therapies such as 5-fluorouracil, photodynamic therapy or liquid nitrogen 
(cryotherapy). Thicker, deeper tumours require surgical excision or radiotherapy. Higher risk lesions, 
or those of the head and neck where there are significant morbidity risks, can be treated using mohs 
Micrographic Surgery where removal is histologically controlled. 
 
Reflectance confocal microscopy (RCM) is a high resolution, non-invasive method for visualising skin 
in cellular detail in-vivo. In studies conducted overseas, confocal microscopy has been shown to be 
highly effective in the diagnosis of Basal Cell Carcinoma [2-5]. Reported sensitivity and specificity for 
RCM in diagnosing BCC range from 83-100% and 79-97% [6-12]  
 
A 2004 study showed that the presence of two or more criteria is 100% sensitive for the diagnosis of 
BCC, and with 4 or more RCM criteria present the specificity was 95.7% and sensitivity was 82.9% 
[6]. 
 
A recent study examined the performance of both the wide field Vivascope 1500 and the narrow field 
Vivascope 3000. While the traditional wide probe RCM (WTP-RCM) provides more coverage of the 
lesional tissue, the smaller-diameter handheld RCM (HH-RCM) allows better access to limited 
anatomic locations [12]. Both instruments are available for this study, and either / both will be used 
depending on anatomic considerations. 
 
Comparison between TWP-RCM vs. HH-RCM was as follows: sensitivity (100% vs. 93%), specificity 
(78% for both probes), positive predictive value (96% vs. 95%), and negative predictive value (100% 
vs. 70%) respectively [12]. Studies have also developed diagnostic criteria for BCC subtypes [11].  
 
Should this diagnostic performance be shown to be replicable in an NHS setting, this would 
represent a significant opportunity to reduce waiting lists and save money, as patients with lower risk 
lesions could be diagnosed and treated during their first presentation to the skin cancer clinic. This 
would improve compliance 
 
Recently, NICE guidance (Nov 2015) was issued regarding the use of RCM in the management of 
skin cancer [13]. 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: 

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…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.” 
 
If RCM is able to accurately diagnose basal cell carcinoma in the majority of lower risk patients then 
RCM would negate the requirement for diagnostic biopsy before listing patients for definitive 
treatment. 
Aims  
 
We propose to undertake a study to determine the diagnostic utility of using RCM for the diagnosis 
of Basal Cell Carcinoma (BCC) in a tertiary referral centre as outlined by the recent NICE report (Nov 
2015). This will allow an assessment of the potential to avoid diagnostic biopsy within the treatment 
pathway. 
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 BCC. 
Study Hypothesis 
The hypothesis of this study is that the use of RCM is would enable a reduction in the number of 
diagnostic biopsies taken before definitive treatment of BCC by at least 50%.  
 
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 
Patients will be recruited from the outpatient clinic of Skin Care Network London. 
Participants 
The aim is to recruit 328 patients, who fit the following criteria: 
 
1. Age 18 years or older. 
2. Patient suspected of having a primary basal cell carcinoma that is a candidate for surgical 
treatment. 
3. Patient willing and able to give informed consent. 
Exclusion criteria 
1. Recurrent or other higher-risk BCC 
2. Patient with basal cell naevus syndrome 
3. Patient treated with hedgehog inhibitor medication (vismodegib) 
4. Patient not suitable for diagnostic biopsy 
5. Location of lesion unsuitable, inaccessible or impractical for scanning with RCM as 
determined by investigator 

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6. Patient with co-morbidities such as other skin disease 
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 lesion requiring biopsy under standard of 
care.  
 
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 (when possible, 48 hours) 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 form should be given to the patient, a copy should be filed in the clinic notes, and the 
original placed in the site file. 
Study Intervention 
Patients will be assessed in clinic by a consultant dermatologist. Patients with a non-pigmented 
lesion suspected to be BCC 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 the images 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. Similarly, the independent trial co-coordinator will 
archive the clinical images anonymously for future reference. 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 will be anonymised. 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 Berlin 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. The clinicians interpreting the confocal microscope 
images will be asked to complete the following questions: 
 
1. RCM description: features of BCC. 
2. RCM diagnosis: BCC (Y/N); degree of certainty (0=low; 1=possible; 2=almost certain) 

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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. 
Statistics 
Summary of statistical methods: 
The 95% confidence interval for the specificity and sensitivity will be calculated for both observers. 
For the confocal microscope to be concluded as having a specificity equal to that of the biopsy the 
lower limit of the 95% confidence interval must not be less than 94%.  Similarly for sensitivity the 
lower limit of the 95% confidence must not be less than 92%. To assess the inter-observer 
agreement the Kappa statistic will be reported alongside the proportion of agreements and 
disagreements. 
 
Sample size calculation 
For a specificity of 97% with a maximum marginal error of 3% for constructing the 95% confidence 
interval a sample size of 125 is required. For a sensitivity of 95% with a maximum marginal error of 
3% for constructing the 95% confidence interval a sample size of 203 is required. A total sample size 
of 328 will be required to test both a specificity of 97% and sensitivity of 95% with a marginal error 
of 3% for both. 
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 in the Dermatology Department, 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 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-003 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-003 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 Skin Care Network Research & Development Department. 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 the Medical Advisory Committee (MAC) of the Skin Care Network. 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 

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occurring though participation in the study, whether from listed side effects, or others yet 
unforeseen. Skin Care 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 Management Group / Steering 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 
 
 
 
 
 

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References: 
1. Levell, N., et al. (2013) "Basal cell carcinoma epidemiology in the UK: the elephant in the room" 
Clinical and experimental dermatology, 38(4), pp. 367-9. 
2. Sauermann, K., et al. (2002) "Investigation of basal cell carcionoma by confocal laser scanning 
microscopy in vivo" Skin Research and Technology, 8(3), pp. 141-7. 
3. González, S. & Tannous, Z. (2002) "Real-time, in vivo confocal reflectance microscopy of basal cell 
carcinoma" Journal of the American Academy of Dermatology, 47(6), pp. 869-74. 
4. Goldgeier, M., et al. (2003) "Noninvasive imaging, treatment, and microscopic confirmation of 
clearance of basal cell carcinoma" Dermatologic surgery, 29(3), pp. 205-10. 
5. Marra, D. E., et al. (2005) "Detection of residual basal cell carcinoma by in vivo confocal 
microscopy" Dermatologic surgery, 31(5), pp. 538-41. 
6. Nori, S., et al. (2004) "Sensitivity and specificity of reflectance-mode confocal microscopy for in 
vivo diagnosis of basal cell carcinoma: a multicenter study" Journal of the American Academy 
of Dermatology, 51(6), pp. 923-30. 
7. Longo, C., et al. (2013) "Is confocal microscopy a valuable tool in diagnosing nodular lesions? A 
study of 140 cases" British Journal of Dermatology, 169(1), pp. 58-67. 
8. Gerger, A., et al. (2006) "Sensitivity and specificity of confocal laser-scanning microscopy for in 
vivo diagnosis of malignant skin tumors" Cancer, 107(1), pp. 193-200. 
9. Eichert, S., et al. (2010) "Diagnosis of cutaneous tumors with in vivo confocal laser scanning 
microscopy" JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 8(6), pp. 400-10. 
10. Guitera, P., et al. (2012) "In vivo confocal microscopy for diagnosis of melanoma and basal cell 
carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases" 
Journal of investigative dermatology, 132(10), pp. 2386-94. 
11. Peppelman, M., et al. (2013) "In vivo diagnosis of basal cell carcinoma subtype by reflectance 
confocal microscopy" Dermatology, 227(3), pp. 255-62. 
12. Castro, R. P., et al. (2015) "Accuracy of in vivo confocal microscopy for diagnosis of basal cell 
carcinoma: a comparative study between handheld and wide-probe confocal imaging" 
Journal of the European Academy of Dermatology and Venereology, 29(6), pp. 1164-9. 
13. NICE (2015)  "VivaScope 1500 and 3000 imaging systems for detecting skin cancer lesions,"  NICE, 
NICE Diagnostic Guidance [DG19].