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NL47392.068.13 Groene thee zalf studie
Topical Sinecatechins Ointment In Treatment
Of Primary Superficial Basal Cell Carcinoma
(July 2014)
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PROTOCOL TITLE ‘Topical sinecatechins in the treatment of primary superficial basal cell
carcinoma: a double blind, randomised, placebo-controlled trial’
Protocol ID NL 47392.068.13
Short title Topical sinecatechins in the treatment of
superficial basal cell carcinoma
EudraCT number 2013-005439-26
Version 3
Date July 15th 2014
Coordinating investigator/project
leader
K.J.A. Frencken, MD
Medical Doctor
Department of Dermatology Maastricht UMC
Email: [email protected]
Tel: 0031 43 3877295
Principal investigator(s) (in
Dutch: hoofdonderzoeker/
uitvoerder)
Dr. N.W.J. Kelleners-Smeets, MD, PhD
Dermatologist
Department of Dermatology Maastricht UMC
Email: [email protected]
Tel.: 0031 43 3877295
Dr. K. Mosterd, MD, PhD
Dermatologist
Department of Dermatology Maastricht UMC
Email: [email protected]
Tel.: 0031 43 3877295
Sponsor (in Dutch:
verrichter/opdrachtgever)
Academisch ziekenhuis Maastricht (azM)
Subsidising party WILL PHARMA
Independent expert (s) I.F. Nagtzaam
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Dermatologist
Department of Dermatology Maastricht UMC
Email: [email protected]
Tel.: 0031 43 3877289
Laboratory sites Dr. V.J.L. Winnepenninckx
Pathologist
Department of Pathology Maastricht UMC
Email: [email protected]
Pharmacy (Manufacturer)
Marketing authorisation holder
Relabeling tubes
MediGene AG (München, Germany)
Michaela Fabry
Director Commercial Operations and Supply
Chain Management
Email: [email protected]
Tel: 0049 89 20 00 33 33 22
WILL PHARMA (Zwanenburg, The Netherlands)
Karel Bouwens
Director Sales and Marketing
Email: [email protected]
Tel: 0031 (0)20 4976551
Apotheek Radboud UMC (Nijmegen, The
Netherlands)
Maren Blonk
Email: [email protected]
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Statistics Dr. P.J. Nelemans
Epidemiologist
Maastricht University
Email: [email protected]
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PROTOCOL SIGNATURE SHEET
Name Signature Date
Head of Department:
Prof. Dr. P.M. Steijlen
Dermatologist
Department of Dermatology Maastricht
UMC
Email: [email protected]
Tel.: 0031 43 3875292
Handtekening Datum
Principal Investigator:
Dr. N.W.J. Kelleners-Smeets, MD, PhD
Dermatologist
Department of Dermatology Maastricht
UMC
Email: [email protected]
Tel.: 0031 43 3877295
Handtekening Datum
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TABLE OF CONTENTS
1. INTRODUCTION AND RATIONALE ................................................................................ 12
2. OBJECTIVES .................................................................................................................... 14
3. STUDY DESIGN ............................................................................................................... 15
4. STUDY POPULATION...................................................................................................... 17
4.1 Population (base)....................................................................................................... 17
4.2 Inclusion criteria ......................................................................................................... 17
4.3 Exclusion criteria........................................................................................................ 17
4.4 Sample size calculation ............................................................................................. 18
5. TREATMENT OF SUBJECTS .......................................................................................... 19
5.1 Investigational product/treatment .............................................................................. 19
5.2 Use of co-intervention ................................................................................................ 19
5.3 Escape medication .................................................................................................... 20
6. INVESTIGATIONAL PRODUCT ....................................................................................... 21
6.1 Name and description of investigational products ................................................... 21
6.2 Summary of findings from non-clinical studies.......................................................... 21
6.3 Summary of findings from clinical studies ................................................................. 22
6.4 Summary of known and potential risks and benefits ................................................ 23
6.5 Description and justification of route of administration and dosage ......................... 23
6.6 Dosages, dosage modifications and method of administration ................................ 23
6.7 Preparation and labelling of Investigational Medicinal Product ................................ 23
6.8 Drug accountability .................................................................................................... 24
7. NON-INVESTIGATIONAL PRODUCT ............................................................................. 25
7.1 Name and description of non-investigational product(s) .......................................... 25
7.2 Summary of findings from non-clinical studies.......................................................... 25
7.3 Summary of findings from clinical studies ................................................................. 25
7.4 Summary of known and potential risks and benefits ................................................ 25
7.5 Description and justification of route of administration and dosage ......................... 25
7.6 Dosages, dosage modifications and method of administration ................................ 25
7.7 Preparation and labelling of Non Investigational Medicinal Product ........................ 25
7.8 Drug accountability .................................................................................................... 25
8. METHODS ........................................................................................................................ 26
8.1 Study parameters/endpoints ..................................................................................... 26
8.1.1 Main study parameter/endpoint ......................................................................... 26
8.1.2 Secondary study parameters/endpoints ............................................................ 26
8.1.3 Other study parameters ..................................................................................... 27
8.2 Randomisation, blinding and treatment allocation .................................................... 27
8.3 Study procedures....................................................................................................... 28
8.4 Withdrawal of individual subjects .............................................................................. 29
8.4.1 Specific criteria for withdrawal (if applicable) ..................................................... 29
8.5 Replacement of individual subjects after withdrawal ................................................ 29
8.6 Follow-up of subjects withdrawn from treatment ...................................................... 30
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8.7 Premature termination of the study ........................................................................... 30
9. SAFETY REPORTING...................................................................................................... 31
9.1 Section 10 WMO event .............................................................................................. 31
9.2 AEs, SAEs and SUSARs ........................................................................................... 31
9.2.1 Adverse events (AEs)......................................................................................... 31
9.2.2 Serious adverse events (SAEs) ......................................................................... 31
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) .......................... 32
9.3 Annual safety report .................................................................................................. 33
9.4 Follow-up of adverse events ..................................................................................... 33
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] ................................... 33
10. STATISTICAL ANALYSIS ............................................................................................. 34
10.1 Primary study parameter(s) ....................................................................................... 34
10.2 Secondary study parameter(s) .................................................................................. 34
10.3 Other study parameters ............................................................................................. 34
10.4 Interim analysis (if applicable) ................................................................................... 35
11. ETHICAL CONSIDERATIONS ..................................................................................... 36
11.1 Regulation statement ................................................................................................. 36
11.2 Recruitment and consent........................................................................................... 36
11.3 Objection by minors or incapacitated subjects.......................................................... 36
11.4 Benefits and risks assessment, group relatedness .................................................. 36
11.5 Compensation for injury............................................................................................. 37
11.6 Incentives ................................................................................................................... 37
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 38
12.1 Handling and storage of data and documents .......................................................... 38
12.2 Monitoring and Quality Assurance ............................................................................ 38
12.3 Amendments .............................................................................................................. 38
12.4 Annual progress report .............................................................................................. 39
12.5 End of study report .................................................................................................... 39
12.6 Public disclosure and publication policy .................................................................... 39
13. STRUCTURED RISK ANALYSIS ................................................................................. 40
13.1 Potential issues of concern ....................................................................................... 40
13.2 Synthesis ................................................................................................................... 42
14. REFERENCES .............................................................................................................. 42
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR ABR form, General Assessment and Registration form, is the application
form that is required for submission to the accredited Ethics Committee (In
Dutch, ABR = Algemene Beoordeling en Registratie)
AE
BCC
Adverse Event
Basal Cell Carcinoma
CA Competent Authority
CCMO Central Committee on Research Involving Human Subjects; in Dutch:
Centrale Commissie Mensgebonden Onderzoek
CV Curriculum Vitae
DSMB
EGCG
Data Safety Monitoring Board
Epigallocatechin-3-gallate
EudraCT
FDA
FFPE
European drug regulatory affairs Clinical Trials
Food and Drug Administration
Formalin-fixed and paraffin-embedded
GCP
H&E
Hh
Good Clinical Practice
Haematoxylin & eosin
Hedgehog
IB Investigator’s Brochure
IC Informed Consent
METC
MUMC
PDT
PTCH1
Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsing commissie (METC)
Maastricht University Medical Centre
Photodynamic Therapy
Patched 1
(S)AE (Serious) Adverse Event
sBCC
SMO
SUFU
Superficial Basal Cell Carcinoma
Smoothened
Suppressor of Fused
SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie
IB1-tekst)
Sponsor The sponsor is the party that commissions the organisation or performance
of the research, for example a pharmaceutical
company, academic hospital, scientific organisation or investigator. A party
that provides funding for a study but does not commission it is not
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regarded as the sponsor, but referred to as a subsidising party.
SUSAR Suspected Unexpected Serious Adverse Reaction
WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen
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SUMMARY
Rationale: Basal cell carcinoma (BCC) is the most frequently occurring nonmelanoma skin
cancer in Caucasians, representing approximately 80% of cases. Incidence rates for men
and women in the Netherlands are 165 and 157 per 100,000 person-years respectively and
are still rising 3-10% annually. In 2009, the lifetime risk for developing a first histologically
confirmed BCC for men was approximately 1 in 5 (21%) and for women it was 1 in 6 (18%).
A simplified classification of BCC includes the following three histological subtypes: nodular
(40,6), superficial (30,7%) and infiltrative BCC (28,7%). Superficial BCCs (sBCCs) differ from
the other subtypes as they tend to appear at a younger age, usually occur on the trunk and
are often multiple. This subtype has the fastest growing incidence.
A characteristic feature of BCCs is their low risk to metastasize, though if untreated they may
induce considerable functional and cosmetic morbidity as they are locally invasive. Surgery is
the first treatment of choice for BCC. However due to the rising incidence and the extensive
workload this entails, a non-invasive topical treatment is often chosen for sBCC as they grow
down from the epidermis into the superficial dermis and therefore are easily accessible for
topical treatment. Photodynamic therapy (PDT), imiquimod cream or 5-fluorouracil cream are
available topical treatments for sBCC however their tumour free survival rates are not equal
to the higher tumour free survival rates of surgical treatment yet. Next to the efficacy, the now
available topical treatments are associated with local skin reactions at the treatment site,
mainly erythema and erosion (imiquimod cream and 5-fluorouracil cream) or pain and
burning sensation (PDT). This creates the need for additional or alternative non-invasive
topical treatments.
Primary Objective: To determine whether topical sinecatechins 10% (Veregen®) ointment
application can lead to a histological regression (efficacy) of a superficial basal cell
carcinoma.
Secondary Objectives: To assess compliance and adverse reactions (safety). To assess
other histological effects with additional immunohistochemic stains; Bcl-2 (anti-apoptosis),
Ki67 (proliferation).
Study design: Clinical double blind, randomized, placebo-controlled intervention trial
Study population: Male and female outpatients, aged 18 years or older without serious
comorbidities of the Dermatology department of MUMC+, The Netherlands, with histological
proven primary superficial basal cell carcinoma ≥ 4mm < 20mm outside the H-zone of the
face and scalp.
Intervention (if applicable): One group receives sinecatechins 10% ointment twice daily for
six weeks and the other group receives placebo twice daily for six weeks.
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Main study parameters/endpoints: The main study parameter is percentage histological
regression of the target tumour. This will be analysed by comparing the proportion of patients
with complete histological regression in the treatment group to placebo group assessed by
independent blinded dermato-pathologists.
Compliance, number of local skin reactions, adverse events and serious adverse events and
histological effects of treatment with sinecatechins 10% ointment versus placebo will also be
assessed.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: First visit, punch biopsy, telephonic consultation and surgical excision
are part of regular care of superficial basal cell carcinoma. Treatment with sinecatechins
ointment or placebo, inclusion visit and two control visits are part of the study.
A potential risk when participating in this study is an allergy for one of the components of the
sinecatechins 10% ointment or placebo.
Local skin reactions at application site represent a special safety issue for topically applied
treatments. Therefore we will evaluate and describe local skin reactions separately from
other adverse events. Local skin reactions can be easily controlled and therefore are
acceptable for the subjects. We do not expect any other risks.
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1. INTRODUCTION AND RATIONALE
Basal cell carcinoma (BCC) is the most frequently occurring nonmelanoma skin cancer in
Caucasians, representing approximately 80% of cases.1 Incidence rates for men and women
in the Netherlands are 165 and 157 per 100,000 person-years respectively and are still rising
3-10% annually.1,2 In 2009, the lifetime risk for developing a first histologically confirmed BCC
for men was approximately 1 in 5 (21%) and for women it was 1 in 6 (18%).2
A simplified classification of BCC includes the following three histological subtypes: nodular
(40,6%), superficial (30,7%) and infiltrative (28,7%) BCC.3,4 Superficial BCCs (sBCCs) differ
from the other subtypes as they tend to appear at a younger age, usually occur on the trunk
and are often multiple.5 This subtype has the fastest growing incidence.
A characteristic feature of BCCs is their low risk to metastasize, though if untreated they may
induce considerable functional and cosmetic morbidity as they are locally invasive. Surgery is
the treatment of first choice for all BCC subtypes. However, due to the rising incidence and
the extensive workload this entails, a non-invasive topical treatment is an often chosen
alternative for surgery for the superficial BCC subtype. As sBCCs grow down from the
epidermis into the superficial dermis, they are easily accessible for topical treatment.
Photodynamic therapy (PDT), imiquimod cream or 5-fluorouracil cream are available topical
treatments for sBCC, however their tumour free survival rates after one year follow-up are
not equal to the higher tumour free survival rates of surgical treatment.6,7 Next to the efficacy,
the now available topical treatments are associated with local skin reactions at the treatment
site, mainly erythema and erosion (imiquimod cream and 5-fluorouracil cream) or pain and
burning sensation (PDT).7 This creates the need for additional or alternative non-invasive
topical treatments.
The main exogenous predisposing risk factor of BCC is ultraviolet light exposure.8 However,
BCC tumourigenesis is multifactorial. The vast majority of BCCs occur sporadically.
Approximately 90% of sporadic BCCs have identifiable mutations in at least one allele of the
patched 1 (PTCH1) gene, an inhibitor of the Hedgehog (Hh) signalling pathway9. This
relieves the inhibition of smoothened (SMO) by PTCH1 and SMO sends signals through a
series of interacting proteins, including suppressor of fused (SUFU), resulting in activation of
the downstream Gli family of transcription factors, leading to proliferation9.
A recent study presents convincing evidence that canonical Wingless-type MMTV integration
site (Wnt) signalling pathway is essential for a tumorigenic response to deregulated Hh
signalling in skin.10 Several earlier studies also report a link between the Hh and Wnt
pathways in BCC.11,12 The canonical Wnt pathway regulates the ability of the β-catenin
protein to accumulate and enter the nucleus, where it interacts with proteins and converts
them into transcriptional activators, leading to proliferation.13
The tumour suppressor gene p53, which controls the intrinsic pro-apoptotic pathway, is
mutated in 40% of sporadic BCCs.14
The active constituents of green tea are promising because of their supposed anti-BCC-
carcinogenesis effects as described by several epidemiological, cell culture and animal
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studies.15,16 The so-called polyphenols known as catechins are the active constituents of
green tea and the catechin epigallocatechin-3-gallate (EGCG) is the major and most active
catechin. EGCG is thought to have a cytotoxic effect on skin cancer cells and has the
availability of inhibition of cell growth and induction of apoptosis.17-21 It is also suggested that
EGCG plays a role in inactivation of β-catenin signalling, an important component of the
WNT pathway.22
Sinecatechins 10% ointment (Veregen®) is a standardized extract of green tea leaves of the
species Camellia sinensis, containing mainly green tea polyphenols, particularly catechins
(more than 85%).23,24 The lead catechin in sinecatechins ointment is EGCG. It is approved by
the US Food and Drug Administration (FDA) for genital warts in adults.
There are no clinical trials on human subjects with topical EGCG on sBCC yet. With this trial
we are the first to try to validate the anti-carcinogenic potentials of topical EGCG in humans
with sBCC. We assess the effectiveness of sinecatechins 10% (Veregen®) versus placebo in
sBCCs. In case of effectivity, dose-response studies and head-to-head-comparison studies
with other topical available treatments will be needed to know the role of topical
sinecatechins 10% ointment as treatment for sBCCs.
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2. OBJECTIVES
Primary Objective: To determine whether topical sinecatechins 10% (Veregen®) ointment
application can lead to a histological regression of a superficial basal cell carcinoma. This
will be analysed by comparing the proportion of patients with complete histological
regression in the treatment group versus the placebo group.
Secondary Objective(s): To assess compliance and adverse reactions (safety). To assess
histological effects with additional immunohistochemical stains; Bcl-2 (anti-apoptosis), Ki67
(proliferation).
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3. STUDY DESIGN
The study will be a double blind, randomized, placebo-controlled intervention trial at the
Maastricht University Medical Centre (MUMC+) in the Netherlands. Patients with a primary,
histologically proven superficial basal cell carcinoma ≥ 4mm and < 20mm outside the H-zone
of the face will be randomly assigned to either sinecatechins 10% ointment or placebo and
instructed to apply the corresponding ointment two times daily for six weeks. Two weeks later
the tumour will be excised. The study will not interfere with clinical practice, because after
this trial all patients will be treated with surgical excision at two to three months after
diagnosis, which is the usual waiting time for excision.
A biopsy is taken to confirm the diagnosis of superficial BCC histologically by pathologists at
the Pathology department of the MUMC+. A superficial BCC is defined as small buds of
proliferating basal cells growing down from the epidermis into the superficial dermis, whilst
maintaining their attachment to the base of the epidermis 3.
Patients will receive instructions to apply sinecatechins 10% ointment twice daily in a thin
layer to the tumour including 5mm surrounding skin. Sinecatechins 10% ointment has to be
applied for six weeks.
The study will proceed according to standardized case report forms, describing which
aspects of the tumour should be examined at the moment of inclusion (inclusion visit), the
first control visit after 3 weeks, the second control visit after 6 weeks and the end visit before
excision in week 8. We planned surgical excision two weeks after the last application of the
study ointments in order to prevent surgical excision has to be postponed due to local
application-site reactions.
Tumour size, local tolerability, adverse events and concomitant medications will be recorded
at each control visit.
Therapeutic surgical excision of the target tumour will be performed two to three months after
diagnosis, for histological evaluation of response. The target tumour will be excised with a
3mm margin surrounding the tumour by different dermatologists at the MUMC+. After regular
histological examination of the resection margins, a histological evaluation of response will
be done by two independent dermatopathologists. Additional immunohistochemical stainings
on punch biopsy (baseline t=0) and excision specimens (t=1) will be done to assess other
histological effects of the treatment. Patients and investigators, including the assessing
pathologists, will be blinded until the end of the study.
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4. STUDY POPULATION
4.1 Population (base)
Male and female outpatients, aged 18 years or older without serious comorbidities of the
Dermatology department of MUMC+, The Netherlands, with histological proven primary
superficial basal cell carcinoma ≥ 4mm and ≤ 20mm in diameter outside the H-zone of the
face will be informed about the study trough informed consent.
One sBCC per patient will be included to ensure independence of observations. For
patients with more than one sBCC, the most accessible for treatment and with the largest
size will be chosen.
Based on the pathological registration in 2009 in MUMC+, we expect an average of 30
new sBCC per month, so recruitment of the required number of patients (n=42, see 4.4
sample size calculation) is considered feasible.
4.2 Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all of the following
criteria:
• Adults aged 18 years or older
• Primary histological proven superficial basal cell carcinoma between ≥ 4mm and ≤
20mm in diameter
• Comorbidities may not interfere with study treatment (evaluated by investigator)
• Capable to understand instructions
4.3 Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from
participation in this study:
• Recurrent sBCC (previous treatment)
• Breast-feeding or pregnant women
• Serious comorbidities
• Use of immunosuppressive medication during
the trial period or within 30 days before
enrolment
• Patients with genetic skin cancer disorders
• Tumour located in the H zone (high-risk area
of face) or hairy scalp (see picture 1)
Picture 1. H-zone of the Face
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4.4 Sample size calculation
It is assumed that about 5% of sBCCs in the placebo group will show histological complete
tumour regression according to the excision specimen, because of a possible biopsy-induced
tumour regression25. At least 50% in the sinecatechins 10% group has to show a complete
tumour regression to consider this treatment as sufficiently effective for further evaluation. A
tumour regression of at least 50% was based on expert opinion, as there is no available
clinical literature of topical sinecatechins for the treatment of sBCC yet. Based on this opinion
a tumour regression in less than 50% of the patients was not found sufficient to conduct
further clinical trials. Based on an alpha=5%, and power of 80%, a total of 38 patients (19
patients per group) are required. This sample size was based on per-protocol analysis and
measured with Fleiss continuity correction method in the following formula:
.
To account for a loss-to-follow-up of 10%, a total of 42 patients (21 patients per group) will be
included.
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5. TREATMENT OF SUBJECTS
5.1 Investigational product/treatment
Intervention:
• Sinecatechins (Veregen®)
• Ingredients: white petrolatum, cera alba (white wax), isopropyl myristate, oleyl
alcohol, propylene glycol monopalmitostearate.
• Active ingredient: Tea polyphenols, particularly catechins (more than 85%). 1g of the
ointment contains 100mg of polyphenon E extract (as dry extract), refined from
Camellia sinensis (L.)O. Kuntze folium (green tea leaf), corresponding to 55-72mg of
(-)-epigallocatechin gallate. 26
• Strength: 10%
• Dosage form: ointment. Brown smooth ointment free from gritty particles.
• Manufacturer: MediGene AG/ Apotheek Radboud UMC
• Marketing authorisation holder: WILL-PHARMA
Placebo:
• Ingredients: white petrolatum, cera alba (white wax), isopropyl myristate, oleyl
alcohol, propylene glycol monopalmitostearate.
• Dosage form: ointment
• Manufacturer: MediGene AG/ Apotheek Radboud UMC
• Marketing authorisation holder: WILL-PHARMA
After randomization, patients apply a thin layer of ointment on the tumour including 5mm
surrounding skin with no occlusive dressing applied. After application, patients are
advised to wash their hands to prevent spreading of the ointment. These actions should
be performed twice daily (morning and evening) for six weeks. Before applying a new
layer patients are advised to wipe off the remnants.
5.2 Use of co-intervention
Concomitant use of other topical treatments on the tumour area is prohibited during the
trial. The use of immunosuppressive medication during the trial or within 30 days before
enrolment is prohibited. Any other oral medication is only allowed after consulting the
principal investigator. Oral intake of green tea is prohibited during the trial or within one
week before enrolment, since in vivo testing of oral administration of green tea on rodents
susceptible on skin cancer showed a significant reduction of new skin tumours and tumour
size.27-29
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Oral paracetamol 500-1000mg, if necessary, respectively every 4 or 6 hours could be
prescribed for local pain due to skin reactions. Topical treatments are not allowed. In case
of severe local skin reactions treatment could be temporarily stopped for a maximum of
one week.
5.3 Escape medication
After end of the study a surgical excision will be performed in intervention group and
placebo group.
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6. INVESTIGATIONAL PRODUCT
6.1 Name and description of investigational products
• Sinecatechins 10% ointment (MediGene/WILL PHARMA)
• Placebo (MediGene/WILL PHARMA)
6.2 Summary of findings from non-clinical studies
The United States Food and Drug Administration has approved the topical ointment
sinecatechins for the treatment of external genital and perianal warts (condylomata
acuminata) in October 200630. The exact mechanism of action of sinecatechins in
eradication of human papillomavirus-induced condylomata acuminata is unknown but may
be due to catechins binding to a number of proteins leading to antioxidative, antiviral,
immunostimulatory and antiproliferative effects. In September 2012 sinecatechins 10%
ointment was registered for the treatment of condylomata acuminate in the Netherlands.
Cancer-preventive effects of EGCG are widely supported by results from epidemiological,
cell culture and animal studies.15,16
Singh et al. showed EGCG had a cytotoxic effect on skin cancer cells without incurring
significant cytotoxicity to normal skin cells under experimental conditions with human skin
cancer cell lines.17 They also suggested inactivation of β-catenin signalling in EGCG-
treated skin cancer cells.17 β-Catenin is an important component of the Wnt pathway.
Yang and colleagues proved that the wingless-type MMTV integration site family (WNT/β-
catenin) pathway is essential in tumorigenic response to deregulated SHH signalling,
confirming crosstalk between the SHH and Wnt pathways in BCCs.10
Meeran et al. showed that topical application of EGCG on wild-type mice resulted in a
significant reduction in UVB-induced skin tumorigenesis in terms of tumour incidence and
tumour multiplicity compared with non-EGCG-treated wild-type mice. This chemo
preventive effect was not observed in Il-12 KO mice treated with topical EGCG, which
suggests that the prevention of photo carcinogenesis by EGCG was mediated, at least in
part, through Il-12 dependent DNA repair.31,32
Mittal et al. also showed inhibition of UV-induced tumour incidence and tumour multiplicity
after topical application of EGCG (1mg/cm2) in hydrophilic cream in SKH-1 hairless mice.
Furthermore, the growth or size of tumours in the EGCG-treated group was significantly
inhibited when measured in terms of total tumour volume/group, tumour volume/tumour-
bearing mouse and average tumour volume/tumour compared to that of the non-EGCG-
treated group.33
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Cyclooxygenase-2 (COX-2) is induced by a large spectrum of growth factors and pro-
inflammatory cytokines in specific pathophysiological circumstances. COX-2 is commonly
overexpressed BCCs, which in turn mediates the expression of PGE234. Katiyar et al.
found that EGCG pre-treated human skin exposed to UVB significantly reduced
prostaglandin metabolites, particularly PGE2.22 Tyring et al. showed an inhibitory effect of
sinecatechins (10µM and 50µM) on cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2), with a slight selectivity of greater inhibition against COX-2.35
Numerous in vitro cell culture studies demonstrated inhibition of cell growth and induction
of apoptosis after treatment with EGCG in concentrations within the range 1-100µM.18-21,36
It is suggested that EGCG inhibits the anti-apoptotic function of Bcl-2 proteins.15
Another possible mechanism by EGCG exercise their anti-tumour property is through the
suppression of the NFκB signalling pathway. NFκB is activated by different stimuli e.g.
inflammatory stimuli, carcinogens and tumourpromotors and induces the expression of
more many genes that suppress apoptosis and induce proliferation and inflammation.15
6.3 Summary of findings from clinical studies
Limited data are currently available from EGCG chemoprevention clinical trials. Several
clinical phase II and III trials showed that the use of topical sinecatechins in treatment of
condylomata acuminata is effective and safe.23,24,37
In two double-blind, multinational randomized controlled trials in adults with external
genital and perianal warts, sinecatechins 10% and 15% ointment (Veregen®), three times
daily for up to 16 weeks was generally well tolerated.23,24 According to pooled data
(n=1005) from the two clinical studies, the majority of adverse events associated with
polyphenon E 10% ointment involved application site and local skin reactions at the
treatment site. The maximum incidence was reached after 4 weeks of treatment in the
sinecatechins 10% group and after two weeks in de sinecatechins 15% group.38 Rates
then decreased gradually until the end of treatment. The most common severe local
reactions were erythema, pruritus, irritation and pain and were reported by 25.8% of the
patients in the sinecatechins 10% group and by 27% of the patients in the sinecatechins
15% group (percentages based on number of patients with no missing data).38 According
to a logistical regression analysis, the complete clearance of all warts was significantly
associated with erosion/ulceration (OR 1.87 [95% CI 1.36, 2.57]) and erythema (OR 1.61
[95% CI 1.16, 2.24]), suggesting that patients who experienced at least one of these
adverse events had a higher likelihood of achieving complete clearance.38
Summarized, both non-clinical and clinical studies show that topical application of
sinecatechins ointment will be safe with only local side-effects and has a potential
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anticarcinogenic effect in BCCs. Further information on the ointment can be found in the
SPC document/IB (Annex D2/D1)26.
6.4 Summary of known and potential risks and benefits
A potential risk for patients in this study is an allergy for one of the components of the
ointment. Sinecatechins 10% and placebo contain propylene glycol monopalmitostearate
which may cause skin irritations and isopropyl myristate which may cause irritation and
sensitization of the skin.26 Application site and local skin reactions (erythema, pruritus,
irritation, pain, erosion/ulceration) and infections may occur. We do not expect any other
risks.
Considering the regular two to three months waiting time for a surgical excision and the
fact that BCCs tend to grow very slowly1, eight weeks is an acceptable period for subjects
to wait for their standard surgical treatment.
6.5 Description and justification of route of administration and dosage
Basal cell carcinoma is the most frequent malignant tumour in Caucasians. This type of
skin cancer rarely metastasizes, but without adequate treatment it will be locally invasive1.
We hypothesize that topical application of sinecatechins results in a higher concentration
at the target tumour in comparison with oral administration. Since sBCCs grow down from
the epidermis into the superficial dermis they are easily accessible for topical treatment.
The available topical treatments imiquimod and 5-fluorouracil cream result in local tumour
destruction by apoptosis, necrosis or stimulation of the immune system. As mentioned
above, the active ingredient (EGCG) in sinecatechins 10% ointment is thought to have a
cytotoxic effect on skin cancer cells and has the availability of inhibition of cell growth and
induction of apoptosis. Next, there is also evidence that EGCG plays a role on the WNT
signalling pathway, activated in BCC and on COX-2, highly expressed in BCC. As EGCG
targets tumour cells in different ways, we hypothesize that application twice daily for 6
weeks will be a reasonable treatment regimen as this is conform the other available
topical self-applicable treatments (imiquimod and 5-fluorouracil) for sBCC.7,39
6.6 Dosages, dosage modifications and method of administration
Patients are instructed to apply a thin layer of the sinecatechins 10% or placebo ointment
twice daily (morning and evening) in a thin layer to the tumour including 5mm of the
surrounding skin. Sinecatechins 10% ointment has to be applied for six weeks. Patients
are advised to wash their hands after each application to prevent spreading of the
ointment.
6.7 Preparation and labelling of Investigational Medicinal Product
Sinecatechins 10% ointment and placebo will be sponsored by WILL PHARMA and
delivered to the MUMC pharmacy. The tubes will be labelled according to the relevant
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GMP guidelines with a preassigned patient number by Apotheek Radboud UMC,
Nijmegen, The Netherlands. Placebo will be of identical colour and consistency as
sinecatechins 10% ointment to ensure blinding. Tubes will be stored under 25 degrees.
6.8 Drug accountability
Tubes will be picked up at the day of inclusion for each patient at the MUMC pharmacy by
the investigator. After randomisation according to the randomisation list, subjects will
receive their tubes by the investigator immediately at their inclusion visit at the
dermatology outpatient clinic at the MUMC. Treatment can start directly and therefore we
can guarantee patients will receive their medication on time. At the end of the study,
subjects are instructed to take the tube to their control visit at week 6. Tubes will be
collected and weighted by the investigator to assess compliance.
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7. NON-INVESTIGATIONAL PRODUCT
7.1 Name and description of non-investigational product(s)
Not applicable.
7.2 Summary of findings from non-clinical studies
Not applicable.
7.3 Summary of findings from clinical studies
Not applicable.
7.4 Summary of known and potential risks and benefits
Not applicable.
7.5 Description and justification of route of administration and dosage
Not applicable.
7.6 Dosages, dosage modifications and method of administration
Not applicable.
7.7 Preparation and labelling of Non Investigational Medicinal Product
Not applicable.
7.8 Drug accountability
Not applicable.
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8. METHODS
8.1 Study parameters/endpoints
8.1.1 Main study parameter/endpoint
The main study parameter is presence or absence of histological regression of the
target tumour according to the excision specimen. This will be assessed by two
independent dermato-pathologists who are blinded to treatment assignment.
8.1.2 Secondary study parameters/endpoints
• Compliance
Data for compliance with the prescribed regimens of either sinecatechins ointment
or placebo will be obtained from a personal diary kept by patients and completed
once a week during treatment. Compliance will be calculated as the number of
applications actually applied by the patient divided by the total prescribed number of
applications. Furthermore tubes will be collected and weighted by the investigator.
• Number of local skin reactions, adverse events and serious adverse events
Local skin reactions at application site represent a special safety issue for topically
applied treatments. Therefore we will evaluate and describe local skin reactions
separately from other adverse events.
At inclusion visit, after punch biopsy (t=0), control visit in week 3, control visit in
week 6 and end visit in week 8 before excision (t=1), tumour size, colour and
objective local skin reactions (ie. Erythema, edema, induration, vesicles,
erosion/ulceration, or other) will be assessed by the investigator.
The maximum incidence of local application site and local skin reactions at the
treatment site was reached after 4 weeks of treatment with topical sinecatechins
10% on condylomata acuminata in the review of Tatti et al. Therefore we scheduled
a first follow-up visit at week 3 to evaluate these local skin reactions and to ensure
continuation of treatment.
Subjective symptoms (ie. Pain, burning, itching, or other) will be assessed from the
personal diary kept by patients once a week during treatment.
Intensity of all skin reactions at the site of applications will be graded as: none, mild
(local skin reaction which can be easily tolerated), moderate (local skin reaction
which is associated with considerable discomfort, but does not prevent usual
activity) or severe (local skin reaction which substantially interferes with the patients’
usual activity).
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Adverse events other than local skin reactions at the application site reported by the
patient will be assessed according to the same grading.
Other adverse events or (suspected) (unexpected) serious adverse events will be
recorded by the investigator.
• Histological effects of intervention on the target tumour area will be assessed with
additional immunohistochemic stains on both punch biopsy (t=0) and surgical
excision specimen (t=1); Bcl-2 (anti-apoptosis), Ki67 (proliferation). The mean
percentage of cells expressing the different antibodies will be analysed by
comparing the proportion of cells expressing antibodies in the intervention group to
placebo group.
The percentage will be assessed at a magnification of 40x (one high power field is
2mm2) by two independent, blinded pathologists using the following criteria:
o Assessment of total tumour area
o Staining pattern
o Percentage of positive stained cells will be estimated and will be ranked on
a semi-quantitive scale as follows:
0, <20%, 1+, 20-40%, 2+, 40-60%, 3+, 60-80%, 4+, >80%
8.1.3 Other study parameters
Baseline characteristics (ie. age, sex, amount of sun-exposure, size and localisation
of the target tumour, medical history and concomitant medication) will be recorded.
8.2 Randomisation, blinding and treatment allocation
Patients will be randomized to either intervention or placebo according to a generated
randomization list using random permuted blocks of four. An independent statistician
will prepare the randomization list. The randomization list will not be available to
investigators or the project team. The tubes will be labelled with a preassigned patient
number according to the randomization list, with each patient allocated to the lowest
available number. Patients and investigators, including the assessing pathologists,
will be blinded to treatment assignment until the end of the study. Placebo will be of
identical colour and consistency as sinecatechins ointment to ensure blinding.
Indications for unblinding are serious suspected adverse events or suspected
unexpected serious adverse events. Only the coordinating investigator is allowed to
break the randomisation code. In all other situations unblinding will take place after
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allocating participants to the relevant analyses populations, just before the primary
statistical analysis.
8.3 Study procedures
First visit:
• Description of tumour by treating doctor: size, colour, dermatological description,
localisation
• Standardized photographs
• Punch biopsy (3mm) of suspect superficial basal cell carcinoma
• Short oral and written information of the study by the outpatient clinic physician
and explanation of phone consultation by the coordination investigator.
After confirmation of the diagnosis of a superficial basal cell carcinoma, patient will
get a phone consultation by the coordinating investigator and receive short
information about the study. If interested written information will be sent by mail and
an appointment will be made within one to two weeks.
Second (inclusion) visit (baseline) t=0:
• Description of tumour by investigator: size, colour, dermatological description,
localisation
• Detailed explanation of the study procedures
• In- or exclusion, in case of inclusion:
o Description of tumour: size, colour, dermatological description, localisation.
The tumour site and appropriate anatomic landmarks will be
mapped using a clear plastic sheet as a template to guide the excision at
the end of the study
o Baseline characteristics
o Standardized photographs with ruler and colour reference chart
o Randomization of the patient into intervention or placebo
o Distribution of study medication according to randomization
o Instruction of patient (see Annex E4.1.)
Third (control) visit (week 3):
• Description of tumour by investigator: size, colour, dermatological description, local
skin reactions
• Adverse events or serious adverse events
• Any change in baseline characteristics
• Standardized photographs with ruler and colour reference chart
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Fourth (control) visit (week 6):
• Description of tumour by investigator: size, colour, dermatological description, local
skin reactions
• Adverse events or serious adverse events
• Any change in baseline characteristics
• Standardized photographs with ruler and colour reference chart
• Investigator will collect and weight the study medication to ensure compliance
Fifth (end) visit (week 8) (t=1):
• Description of tumour by investigator: size, colour, dermatological description, local
skin reactions
• Adverse events or serious adverse events
• Any change in baseline characteristics
• Standardized photographs with ruler and colour reference chart
• Surgical excision with a standard 3mm margin
• Investigator will receive patients diary
First visit, punch biopsy, telephonic consultation and surgical excision are part of
regular care of superficial basal cell carcinoma. Treatment with sinecatechins
ointment or placebo, inclusion visit and two control visits are part of the study.
All tissue samples will be formalin-fixed and paraffin-embedded (FFPE). As part of
regular care, 4µm sections will be stained with haematoxylin & eosin (H&E) to confirm
histological diagnosis and tumour regression in case of excision.
All tissues will follow the same protocol to improve the reliability of the staining
assessment. For each antibody, tissues known to have strong expression of the
respective protein will be included as a positive control. Negative controls, in which
the primary antibody was not added, will be included in all experiments.
8.4 Withdrawal of individual subjects
Subjects can leave the study at any time for any reason if they wish to do so without
any consequences. The investigator can decide to withdraw a subject from the study
for urgent medical reasons.
8.4.1 Specific criteria for withdrawal (if applicable)
Not applicable
8.5 Replacement of individual subjects after withdrawal
After withdrawal of a subject we will not replace the subject by a new subject.
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8.6 Follow-up of subjects withdrawn from treatment
Subjects withdrawn from therapy will be followed till surgical excision.
8.7 Premature termination of the study
The study will only be terminated if many patients experience suspected unexpected
serious adverse events or serious adverse events. In case the study will be
terminated prematurely the coordinating investigator will inform the METC within 15
days. Since clinical studies with sinecatechins ointment show it is safe in use, with
minimal serious adverse events we don’t expect premature determination to occur.
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9. SAFETY REPORTING
9.1 Section 10 WMO event
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
subjects and the reviewing accredited METC 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 METC, except insofar as suspension would jeopardise the subjects’
health. The investigator will take care that all subjects are kept informed.
9.2 AEs, SAEs and SUSARs
9.2.1 Adverse events (AEs)
Adverse events are defined as any undesirable experience occurring to a subject
during the study, whether or not considered related to [the investigational product /
the experimental intervention]. All adverse events reported spontaneously by the
subject or observed by the investigator or his staff will be recorded.
9.2.2 Serious adverse events (SAEs)
A serious adverse event is any untoward medical occurrence or effect that at any
dose:
- 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;
- Any other important medical event that may not result in death, be life threatening,
or require hospitalization, may be considered a serious adverse experience when,
based upon appropriate medical judgement, the event may jeopardize the subject
or may require an intervention to prevent one of the outcomes listed above.
The sponsor will report the SAEs through the web portal ToetsingOnline to the
accredited METC that approved the protocol, within 15 days after the sponsor has
first knowledge of the serious adverse events.
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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 event. This is for a preliminary report with another
8 days for completion of the report.
9.2.3 Suspected unexpected serious adverse reactions (SUSARs)
Adverse reactions are all untoward and unintended responses to an investigational
product related to any dose administered.
Unexpected adverse reactions are SUSARs if the following three conditions are met:
1. the event must be serious (see chapter 9.2.2);
2. there must be a certain degree of probability that the event is a harmful and an
undesirable reaction to the medicinal product under investigation, regardless of
the administered dose;
3. the adverse reaction must be unexpected, that is to say, the nature and severity
of the adverse reaction are not in agreement with the product information as
recorded in:
- Summary of Product Characteristics (SPC) for an authorised medicinal
product;
- Investigator’s Brochure for an unauthorised medicinal product.
The sponsor will report expedited the following SUSARs through the web portal
ToetsingOnline to the METC:
SUSARs that have arisen in the clinical trial that was assessed by the METC;
SUSARs that have arisen in other clinical trials of the same sponsor and with the
same medicinal product, and that could have consequences for the safety of the
subjects involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be
submitted once every half year to the METC. This line-listing provides an overview
of all SUSARs from the study medicine, accompanied by a brief report highlighting
the main points of concern.
The expedited reporting of SUSARs through the web portal ToetsingOnline is
sufficient as notification to the competent authority.
The sponsor will report expedited all SUSARs to the competent authorities in other
Member States, according to the requirements of the Member States.
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The expedited reporting will occur not later than 15 days after the sponsor has first
knowledge of the adverse reactions. For fatal or life threatening cases the term will
be maximal 7 days for a preliminary report with another 8 days for completion of the
report.
Indications for unblinding are serious suspected adverse events or suspected
unexpected serious adverse events. Only the coordinating investigator is allowed to
break the randomisation code.
9.3 Annual safety report
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year
throughout the clinical trial, a safety report to the accredited METC, competent authority,
and competent authorities of the concerned Member States.
This safety report consists of:
a list of all suspected (unexpected or expected) serious adverse reactions, along with
an aggregated summary table of all reported serious adverse reactions, ordered by
organ system, per study;
a report concerning the safety of the subjects, consisting of a complete safety analysis
and an evaluation of the balance between the efficacy and the harmfulness of the
medicine under investigation.
9.4 Follow-up of adverse events
All AEs 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.
SAEs need to be reported till end of study within the Netherlands, as defined in the
protocol
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee]
Not applicable.
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10. STATISTICAL ANALYSIS
10.1 Primary study parameter(s)
Primary study outcome is histological regression of the target tumour on the excision
specimen as assessed by two independent dermatopathologists. Any discrepancy will be
resolved by consensus. The proportions of patients with complete histological regression
in the treatment group and placebo group will be compared and tested for statistical
significance using the Chi-square test. Both an intention-to-treat and per protocol analysis
will be performed. Missing data will be documented and patients loss-to-follow-up will be
analysed in the intention-to-treat-analysis. Reported P values will be two-sided and P
values ≤ 0.05 are considered statistically significant. Statistical analysis will be performed
by using SPSS version 20.0 software.
10.2 Secondary study parameter(s)
Compliance will be calculated as the number of applications actually applied by the
patient divided by the total prescribed number of applications. This ratio will be multiplied
by 100 to calculate compliance percentages. Mean compliance percentages will be
compared between the randomized groups and will be tested for significance using the t-
test for independent samples (if normally distributed) or the Mann-Whitney U test (if not
normally distributed).
Proportions of patients with local skin reactions and adverse events will be compared
between randomized groups and will be tested for statistical significance using the Chi-
square test.
For all outcome parameters, both an intention-to-treat and per protocol analysis will be
performed. Missing data will be documented and patients loss-to-follow-up will be
analysed in the intention-to-treat-analysis. Reported P values will be two-sided and P
values ≤ 0.05 are considered statistically significant. Statistical analysis will be performed
by using SPSS version 20.0 software.
10.3 Other study parameters
Baseline characteristics will be presented to enable assessment of comparability between
the intervention and placebo group. Nominal and categorical variables will be presented
as proportions and absolute number and continuous variables as mean ± standard
deviation (SD) or median and range.
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10.4 Interim analysis (if applicable)
We do not plan to perform an interim analysis since topical sinecatechins 10% ointment is
a well-known safe drug and the intervention period is only six weeks.
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11. ETHICAL CONSIDERATIONS
11.1 Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki
version 10 October 2013 and in accordance with the Medical Research Involving Human
Subjects Act (WMO).
11.2 Recruitment and consent
At patients first visit at the Dermatology department the outpatient clinic physician will
give short oral and written information of the study and explains the phone consultation
will be done by the coordinating investigator. When diagnosis of superficial basal cell
carcinoma is histologically confirmed by punch biopsy, the patient gets a phone
consultation with the coordinating investigator and is shortly informed about the study. If
interested, the patient will receive additional written patient information by mail. Patients
will get a consideration period of at least 1 week in which they can decide to participate or
not, followed by an appointment with the coordinating investigator. During consideration
period patients can contact the investigator/ independent physician with any question.
At the second (inclusion) visit, patients will be further informed about the study and if
willing to participate, they will sign informed consent at the same time with the
investigator. A copy of the signed subject informed consent form shall be given to each
study patient. The signed subject informed consent forms will be kept at the
investigational site on a secure location.
For the patient information letter see Annex E1 and for the informed consent form see
Annex E2.
11.3 Objection by minors or incapacitated subjects
Not applicable.
11.4 Benefits and risks assessment, group relatedness
Participation requires patients to apply the supplied ointment (sinecatechins 10% or
placebo) twice daily for six weeks. Participation in the study will take two times 5 minutes
a day. The first and fifth visit at the hospital are regular visits, even patients not
participating in the study should visit at the hospital at these moments. The second
(inclusion) and third and fourth (control) visits will be extra study visits for study patients.
As described above, a potential risk when participating in this study is an allergy for one
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of the components of the sinecatechins 10% ointment or placebo. Furthermore, local skin
reactions due to the ointment are possible but can be easily controlled.
To confirm diagnosis, a 3mm punch biopsy is taken after injection of local anaesthetic
which is briefly painful. Patients not included in the study will also have a punch biopsy as
part of regular care. Subsequently, the tumour will be regularly excised in total after eight
weeks.
11.5 Compensation for injury
The sponsor/investigator has a liability insurance which is in accordance with article 7,
subsection 6 of the WMO.
The sponsor (also) has an insurance which is in accordance with the legal requirements
in the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for
Clinical Research in Humans of 23th June 2003). This insurance provides cover for
damage to research subjects through injury or death caused by the study.
1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for
all subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the
organisation for all damage disclosed by scientific research for the Sponsor as
‘verrichter’ in the meaning of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4
years after the end of the study.
For further information see the insurance text: Annex G1.
11.6 Incentives
Patients will receive a refund of the travel expenses.
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION
12.1 Handling and storage of data and documents
Patient data are stored in a protected computer file and will be processed anonymously. A
subject identification code list is used to link the data to the subject. Coding is not based
on patients initials or birth-date. Patient material will be coded in the same way. The key to
the data and patient material code both will be safeguarded by the pharmacist.
All data, photographs and slides for the immunohistochemical stains Ki-67 en Bcl-2 will
be stored for a maximum of 15 years after the end of the trial for further future research.
Punch biopsy and excision specimens will be stored at the Pathology Department as part
of clinical routine. During and after the study, the coordinating and principal investigators
will have access to patient material and data. Patients will be informed and asked for their
permission for further future analysis in the informed consent form (Annex E2). Future
analysis with punch biopsy and excision specimens will be performed only if patients and
the medical ethics committee gave their permission.
12.2 Monitoring and Quality Assurance
Monitoring will be performed by the Clinical Trial Centre Maastricht and will be based on
the risk classification. The degree of monitoring will depend on this classification.
12.3 Amendments
A ‘substantial amendment’ is defined as an amendment to the terms of the METC
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 METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the
competent authority, but will be recorded and filed by the sponsor.
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12.4 Annual progress report
The sponsor/investigator will submit a summary of the progress of the trial to the
accredited METC 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.
12.5 End of study report
The sponsor will notify the accredited METC and the competent authority of the end of
the study within a period of 90 days. The end of the study is defined as the last patient’s
last visit.
In case the study is ended prematurely, the sponsor will notify the accredited METC and
the competent authority within 15 days, 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 METC and the Competent Authority.
12.6 Public disclosure and publication policy
There are no limitations with regard to publication of the results of the study. The findings
will be published in international peer-reviewed open access journals and will be
communicated in (inter)national conferences to scientists/physicians. In exceptional
cases, if the public interest requires, we will spread results via popular media.
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13. STRUCTURED RISK ANALYSIS
13.1 Potential issues of concern
a. Level of knowledge about mechanism of action
There are numerous epidemiological, cell culture and animal studies about the possible
effects of EGCG, the major catechin in sinecatechins ointment, on skin cancer.
Possible mechanisms of sinecatechins ointment on superficial basal cell carcinoma are
described in chapter 6.2 of this protocol and include inhibition of cell growth and induction
of apoptosis18-21,37, inactivation of β-catenin signalling17, prevention of
photocarcinogenesis31,32, at least in part, through Il-12 dependent DNA repair and an
inhibitory effect on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), with a
slight selectivity of greater inhibition against COX-235.
b. Previous exposure of human beings with the test product(s) and/or products with a
similar biological mechanism
Previous exposure of human beings with the test products is described in several
studies.23,24 The exact mechanism of action of sinecatechins in eradication of human
papillomavirus-induced condylomata acuminata is unknown but may be due to catechins
binding to a number of proteins leading to antioxidative, antiviral, immunostimulatory and
antiproliferative effects.
Topical application of sinecatechins 10% ointment on sBCC in human beings was never
tested.
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo
human cell material?
Since most human BCC arise due to PTCH mutations, PTCH mutant mice certainly
represent the closest model to the human condition.40 PTCH+/- mice (mice lacking one
patched gene) might be a valuable tool to analyze efficacy of new anti-BCC drugs,
however due to the mode of BCC induction by exposure to ionizing radiation (IR) or
ultraviolet radiation (UV), the molecular mechanisms responsible for BCC formation are
probably very heterogeneous.40 IR or UV radiation in PTCH+/- mice results in nodular,
superficial as well as infiltrative BCC subtypes, trichoblastomas and also squamous cell
carcinoma (SCC), a more aggressive form of skin cancer with a potential to metastasize.40
Because UV or IR radiation in mice results in different BCC subtypes or other forms of
skin cancer, this inhibits investigation of topical sinecatechins 10% ointment on sBCC
subtypes specifically. There are no human ex-vivo tests specific for skin with sBCC
treated with topical application of sinecatechins 10% during 6 weeks available.
d. Selectivity of the mechanism to target tissue in animals and/or human beings
Singh et al. showed EGCG had a cytotoxic effect on skin cancer cells without incurring
significant cytotoxicity to normal skin cells under experimental conditions with human skin
cancer cell lines.17
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e. Analysis of potential effect
“Preclinical safety data were gained with the extract from green tea leaves or the higher
strength Veregen 15% ointment. No special hazard for humans was revealed concerning
safety pharmacology, genotoxicity and carcinogenic potential (herbal preparation). In
conventional studies of repeated dose toxicity, no effects beside the local effects could be
seen using the Veregen 15% ointment. Results are fully applicable for the lower strength
Veregen 10% ointment”.26 See SPC/IB document (Annex D2/D1).
In two double-blind, multinational randomized controlled trials in adults with external
genital and perianal warts, sinecatechins 10% and 15% ointment (Veregen®), three times
daily for up to 16 weeks was generally well tolerated with only local side-effects.23,24
f. Pharmacokinetic considerations
The pharmacokinetics of topically applied extract from green tea leaves have not been
sufficiently characterized.26
g. Study population
Male and female outpatients, aged 18 years or older of the dermatology department of the
MUMC+, The Netherlands, with histological proven primary superficial basal cell
carcinoma ≥ 4mm < 20mm outside the H zone of the face or hairy scalp will be informed
about the study trough informed consent. Breast-feeding or pregnant women, patients
using immunosuppressive medication during the trial period or within 30 days before
enrolment, with genetic skin cancer disorders or with a tumour located in the H zone
(high-risk area of face) or hairy scalp are excluded from study.
h. Interaction with other products
Since sinecatechins 10% ointment is applied topically and concomitant use of other
topical treatments on the tumour area and the use of immunosuppressive medication
during the trial or within 30 days before enrolment is prohibited we do not expect potential
pharmacokinetic interactions.
i. Predictability of effect
Topical sinecatechins 10% ointment on sBCC in human subjects was never tested before.
Potential biomarkers for effect of topical sinecatechins 10% in human are Ki67, a
proliferation marker and Bcl-2, an anti-apoptosis marker. These additionally
immunohistochemic stains will be used to show anti-proliferative and pro-apoptotic effects
of sinecatechins 10% ointment on sBCC. The immunohistochemic stains will be analyzed
by two independent dermato-pathologists by comparing the proportion of cells expressing
antibodies in the intervention group to placebo group.
j. Can effects be managed?
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Oral paracetamol 500-1000mg, if necessary, respectively every 4 or 6 hours could be
prescribed for pain due to local skin reactions. In case of severe local skin reactions
treatment could be temporarily stopped for a maximum of one week.
13.2 Synthesis
Male and female outpatients, aged 18 years or older without serious comorbidities with a
primary sBCC ≥4mm and <20mm outside the H zone of the face are included. This
subtype of BCC is a low risk BCC and has an extremely low risk to metastasize. As
described above, a potential risk when participating in this study is an allergy for one of
the components of the sinecatechins 10% ointment or placebo.
Local skin reactions at application site represent a special safety issue for topically applied
treatments. Therefore we will evaluate and describe local skin reactions separately from
other adverse events. Local skin reactions can be easily controlled and therefore are
acceptable for the subjects. We do not expect any other risks.
14. REFERENCES
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