An open, multicentre, randomised, inter-individual comparative, prospective clinical trial with MD-3511356 versus standard sun protection measures in immunosuppressed outpatients after solid organ transplantations for the prevention of UV-induced infections and carcinogenic skin alterations

2. BACKGROUND INFORMATION

2.1 Name and Description of the Investigational Medical Device
MD-3511356 is a sun protection product for prophylaxis of some UV-caused skin
damages. It has the status of a Medical Device. MD-3511356 is a further
development of the medical device Daylong actinica® that is available as a
CE-marked product on several markets. The UV-filters have been changed in order
to get a better UVA-protection and to meet the international norms. The product
is a lotion, previously filled in tubes and now in dispensers.
Whereas most commercially available sunscreen products consist of UV-reflecting
metal-oxides (zinc, titanium), Spirig sunscreen products consequently use
liposomal drug delivery mechanisms. The latter promotes adequate delivery of
barely visible UV-absorbing filters into the upper part of the epidermis
(stratum corneum) and ensures lasting, waterproof UV-protection (> 12 hrs) with
a minimum of unwanted side effects (greasiness, whitening effect, sticky
feeling on the skin etc). Especially the sustainable protective effect of
UV-filters in combination with the low rate of unwanted side effects ensures a
high acceptance and compliance of patients in need of permanent UV-protection.
Further to the above mentioned UV-protective measures, the newly formulated
sunscreen has superior cosmetic features as a moisturizer and, because of
comparably low oiliness, should be favourable for patients with CNI (i.e.
cyclosporine) dominated immunosuppression regiments, suffering from associated
seborrhoeic facial skin. The vehicle is free from fragrances.

2.2 Rationale for the Present Trial
Sunscreens were described to delay, if not prevent, two major types of skin
malignancies:
1. UV-radiation-induced skin malignancies
2. UV-radiation-induced photo-immunosuppression (i.e. depletion of certain
T-cell subtypes and Langerhans cells, increase of IL-10).
Whereas the first characteristic is of specific interest for the prevention of
skin cancer in younger transplant-patients, prevention against the
immunosuppressive aspect of UV-radiation may help to decrease rapid
proliferation of early forms of skin cancer, especially actinic keratoses (AK),
invasive squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), but also
skin infections (viral warts and others).
Due to above described cosmetic side effects, the compliance regarding the
medically advised daily use of sunscreens even in high-risk patients is low,
well accepted liposomal sunscreens specifically designed for the requirements
of targeted high risk patients could offer a promising alternative for the
prevention of subsequent skin cancers.
A first, single-centre, case-control pilot study with Daylong actinica® showed
a decrease of AK and a prophylaxis against development of subsequent SCC (and
partially BCC) in patients applying liposomal sunscreens on a regular basis for
at least 24 months. However, larger, multicentre trials are needed to prove
sufficient prophylactic effects for different skin types in differently
UV-exposed countries across Europe for this high-risk population of chronically
immuno-compromised patients.
2.2.1 Summary of findings from non-clinical and clinical trials
2.2.1.1 Findings from non-clinical trials
No particular toxicological studies have been conducted with the product. Data
obtained in animals regarding acute and chronic toxicity as well as from
reproductive and mutagenic/carcinogenic studies demonstrate that the
excipients/individual constituents should be almost free of toxicity if
administered in the recommended manner.
The photoallergic potential of the product was tested according to a standard
protocol in volunteers. It could be demonstrated that the product exhibits
neither allergic nor photoallergic potential.
In a further trial the irritancy and sensitisation potential of the product
have been evaluated in healthy volunteers. After multiple applications the
product has not induced sensitisation reactions and it was classified as very
well tolerated. The phototoxic potential of a single application of the product
was tested in volunteers also according to a standard protocol. Neither an
irritating nor a phototoxic potential could be detected.
2.2.1.2 Findings from clinical trials
A preliminary study was performed with 5 different eligible sunscreen products
(SPF > 50, High-UVA absorption) to elicit a sunscreen product preference. 9 out
of 12 randomly recruited organ transplant recipients (OTRs) (4 kidney (KTR), 4
heart (HTR), 4 liver (LTR) transplant patients) expressed a preference for a
liposomal sunscreen product (Daylong actinica®). Thereafter, two groups of 60
OTRs (verum and control) of a specialised transplant outpatient dermatology
unit were recruited. Patients in the control group received aside from the
initial sun protection education no further support and no free sunscreen
products. All patients underwent full body examination prior and throughout the
study. Skin cancers from the past medical history since receiving the graft as
well as during the study were documented. Within the 24 month study interval 42
of the 120 patients developed 82 new AK (-102 verum vs. 82 control; p < 0.01,
mean difference 3.07, 95% Confidence Interval of the difference [2.47-3.65]),
eight (8) new invasive SCC (0 vs. 8; p < 0.01, mean difference 0.133
[0.03-0.23]) and 15 BCC (6 vs. 9; n.s., mean difference 0.05 [-0.08- 0.17]).
With an average of 5.6 applications per week, year round for a total of 24
months the compliance and acceptance of the previously chosen liposomal
sunscreen was excellent. In spite of equal numbers of AK at baseline a marked
difference in favour of the intent-to-treat sunscreen group was recorded after
24 months (89 vs. 273; p < 0.01, mean difference 3.07 [1.76-4.36]). The lesion
count was significantly lower as compared to the initial visit (89 vs. 191; p <
0.01, mean difference 1.7 [0.68-2.72]), indicating even remission of AK under
sunscreen protection. There were no statistically significant differences in
the incidence of BCC, but the proportion of patients who developed a SCC was
markedly reduced in the intent-to-treat group.
In a monocentric placebo controlled study with 10 patients Daylong actinica®
has been shown to exhibit excellent skin-protective effects after induction of
a polymorphous photodermatosis by UV-Radiation. It could be convincingly
demonstrated that adverse dermatological reactions such as infiltrated
erythema, pruritus and development of papules were completely prevented in all
persons.
2.2.1.3 Risk-Benefit Assessment
Organ transplant recipients (OTR) are highly susceptible to develop
non-melanoma skin cancer, such as actinic keratoses, invasive squamous cell
carcinomas and basal cell carcinomas. Between 35-50% of OTR develop one or more
skin cancers by the tenth year following organ transplantation. The skin
cancers are mainly localised on sun-exposed areas (face, head, neck, trunk,
hands and arms) in both immuno-competent and immuno-compromised populations.
OTR have the opportunity to modify their skin cancer risk by reducing exposure
to UV-radiation through the use of sunscreen products, sun-protecting clothing
or by avoiding direct sun exposure.
Both the non-clinical trials with volunteers and the clinical trials with
patients support the low sensitisation and skin irritation potential of the
product. The toxicity profile of Daylong actinica® does not give rise to safety
concerns. Clinically insignificant irritation potential may be suggested after
administration to the skin. No deaths, serious adverse or other significant
adverse events were seen in any of the studies. Postmarketing surveillance data
confirmed the safety and tolerability profile of Daylong actinica® (59 reports;
one allergic reaction, 45 irritation reactions and 13 further adverse
reactions).
Daylong actinica® is an essential treatment for people who are at risk for
non-melanoma skin cancers. Taking into consideration the chemical structure and
the toxicological profile of the ingredients as well as the results of finished
product Daylong actinica® may be considered safe also during long term
application when used as recommended. It can be therefore concluded that the
therapeutic benefit of the Daylong actinica® formulation outweighs by far
possible risks. MD-3511356 is a further development of Daylong actinica® in
order to meet the patients* needs in a better way.

2.3 Description of the Route of Administration, Dosage Form, Dosage Regimen and
Treatment Period
For Daylong actinica®, the original medical device and precursor product of
MD-3511356, the official instruction for use detains under *instruction on
application and dosage* that the lotion should be applied every morning before
exposing to the sun to those areas of skin that are or could be exposed to
direct sunlight. So the normal dosage recommendation for the product is once
daily in the morning. After applying, one should wait a few minutes to allow
the lotion to be absorbed into the skin. In this case the product protects for
several hours in a maximal way. Reapplying the lotion is only considered
following longer periods in the water or having been sweating heavily. The same
dosage recommendation is valid for MD-3511356, too.
During the clinical investigations of Daylong actinica® a dose of 2 mg lotion
for each cm2 skin surface showed therapeutic efficacy. Therefore for an area of
100 cm2 0.2 g lotion should be used. Based on this assumption, a single dose of
0.5 g lotion (1 pump out of the dispenser) is adequate to treat an area of 250
cm2 (i.e. one hand).
MD-3511356 is provided as a lotion in dispensers of 80 g. The duration of
treatment is 2 years. MD-3511356 has to be applied every day without exception.

2.4 Compliance Statement
This clinical trial will be conducted in compliance with this Clinical
Investigation Plan, the international guidelines for Good Clinical Practice
(GCP) and the applicable local and international regulatory requirements.
The clinical trial follows the European Directive 2001/20/EC on the
approximation of the laws, regulations and administrative provisions of the
Member States relating to the implementation of Good Clinical Practice in the
conduct of clinical trials on medical products for human use and the harmonised
European standards EN ISO 14155-1 and 14155-2. The device used within the
clinical trial is developed according to the European Medical Devices Directive
93/42/EEC.

2.5 Description of Trial Population
At total of 300 female and male solid organ-transplant recipients (>= 40 years)
with a history of kidney- (including pancreas-), liver-, lung- or
heart-transplantation are planned to be enrolled into this clinical trial.

2.6 Literature Background for the Trial
Organ transplant recipients have a particularly high rate of squamous cell
carcinoma with a relative risk approximately 100-fold higher than the
immuno-competent population.
Studies with renal transplant recipients show that about 93.5% of all squamous
cell carcinomas occurring on the traditional *sunny-terraces* of the body
mainly head, neck, dorsum of the hands, and forearms. Basal cell carcinoma is
increased *only* by a factor of 10 in organ transplant recipients. Whereas, in
immuno-competent patients, only approximately 10% of individual lesions of
actinic keratosis advance to invasive squamous cell carcinoma during a 5-10
year time frame, in organ transplant recipients the rate of progression of
actinic keratosis is apparently accelerated (months) and the incidence of
progression higher. Apart from the direct effect of UV radiation causing DNA
damage in keratinocytes, increasing evidence supports the hypothesis that UV
radiation has also a negative effect on the local immuno-surveillance of
exposed skin and even on systemic immunity. UV radiation inhibits the function
of antigen-presenting cells (Langerhans cells) and T-cells with suppressor
activities. This inhibition enables previous UV radiation-induced mutant clones
to escape from local immuno-surveillance and to proliferate. Systemic
immuno-suppression is mainly supported by the induction and release of IL-10 by
keratinocytes caused by UV radiation.
UV radiation is not only the major risk factor for non-melanoma skin cancer in
organ transplant recipients, but it is presumably the only factor which is
*avoidable* in the immuno-compromised organ transplant recipients. Two studies
from Australia have shown good evidence that sunscreen products use reduces the
prevalence of actinic keratosis and of recurrent squamous cell carcinoma in
immuno-competent populations. Sun avoidance and sun protection measures,
including sunscreen products application techniques, are usually cornerstones
of dermatological education programmes designed for organ transplant recipients
worldwide. It has been speculated, that the reason for the early
post-transplant development of skin cancer in organ transplant recipients,
particularly in elderly patients, is the fact that *dormant* precursor cells of
squamous cell carcinoma and lesions (including subclinical actinic keratosis)
are frequent, even in the middle-aged population. As long as these earliest
steps towards invasive squamous cell carcinoma are well controlled by the local
cutaneous immune system, they remain clinically invisible. In contrast, in
individuals who are chronically or repetitively exposed to UV radiation, and in
systemically immuno-compromised patients such as organ transplant recipients
and haemodialysis patients etc as well as the elderly with impaired
immuno-surveillance, progression to an invasive squamous cell carcinoma occurs
in a relatively short time frame. This fact highlights the need to protect the
remaining cutaneous immunity against the UV hazard. This provides the rationale
that such primary and even secondary prevention should be part and parcel of
the management of organ transplant recipients.
The fact that sun protection can influence previtamin D3 synthesis in skin and
the question about the importance of optimal vitamin D levels for general
health are a current hot topic both in popular press and in scientific
literature, although this still remains currently controversial. In all
patients with regular sun protection, it is believed that vitamin D levels
should be monitored regularly and should be substituted per os to prevent
vitamin D deficiency. On the other hand, excessive sun exposure may also have
unwanted side effects on vitamin D metabolism: vitamin D synthesis is maximal
at suberythemal UV doses and further UV exposure only increases the conversion
of previtamin D3 to lumisterol and tachysterol, both biologically inert
compounds. Furthermore, continued sun exposure degrades the active form of the
photolabile Vitamin D3.
Taken together, there is good evidence that regular sunscreen products use
could prevent immuno-competent patients from developing UV-induced skin
cancers. However, there is only one pilot single centre study published so far
indicating that daily sun protection is also able to prevent SCC, and to a
lesser extend BCC in organ transplant recipients and could even lead towards a
decrease of AK in this high-risk patient group.

3. TRIAL OBJECTIVES AND PURPOSE

3.1 Primary Objective
The primary objective is the prevention of actinic keratoses and squamous cell
carcinomas by local application of MD-3511356 in comparison to standard sun
protection measures in immuno-suppressed solid organ transplant recipients.

3.2 Secondary Objective
The secondary objective is the prevention of actinic keratoses and carcinogenic
skin alterations by local application of MD-3511356.

3.3 Safety Objectives
Safety will be assessed by means of treatment related adverse events, local
tolerability and Vitamin D serum levels (25-OH-Vitamin D3).

4. TRIAL DESIGN
4.1 Endpoints
All efficacy endpoints will primarily be assessed on treated target areas
(face, scalp, head, neck, forearms and hands) only (with exception of SCC),
within the period of two years.
4.1.1 Primary efficacy endpoint
• New actinic keratoses or squamous cell carcinomas
4.1.2 Secondary efficacy endpoints
Secondary efficacy endpoints will be:
• New actinic keratoses, squamous cell carcinomas or basal cell carcinomas
• New squamous cell carcinomas
• New squamous cell or basal cell carcinomas


4.1.3 Exploratory efficacy endpoints
Exploratory efficacy endpoints will be:
• New basal cell carcinomas
• Actinic keratoses (numbers within two years and at the end of the two years
period)
• Other new skin tumours
• New warts
• Skin infections
4.1.4 Safety endpoints
• Related adverse events
• Local tolerability
• Vitamin D serum levels
4.2 Design of Trial
4.2.1 Trial design and schedule of assessments
The clinical trial is designed as an open-label, randomised, comparative,
multicentre trial comparing UV-protection treatment with MD-3511356 versus
standard sun protection measures (inc. commercially available UV-protection
sunscreen products) in immunosuppressed solid organ transplant recipients for
24 months. All patients considered for screening must have a confirmed history
of kidney- (with or without pancreas), liver-, lung- or heart-transplantation.
After all the inclusion and the exclusion criteria have been checked and all
screening procedures have been performed, the patient will be elected for trial
participation by the Investigator. Recruitment phase is expected to last 3
months. Treatment per patient will be 24 months.
A minimum number of 20 patients need to be enrolled in each centre. A total of
300 patients is planned to be randomly assigned in a ratio of 2:1 to one of two
treatment arms:
Group A: Patients will receive detailed information on standardised sun
protection measures. Additionally, they will be provided free of charge with
MD-3511356 for application to sun exposed skin areas once daily in the morning
for 24 months. MD 3511356 lotion will be applied topically on the sun-exposed
skin areas (face, neck, head, forearms and hands) in doses corresponding to the
surface extent (see chapter 6.1). The dispensers will be provided with a dosage
pump to allow application of reproducible amounts (each pump 0,5 g).
Group B: Detailed information on standardised sun protection measures and
application of self-provided sunscreen products. The Investigator may decide on
an individual reimbursement of patient's expenditure (out of the centre's
budget).
Trial procedures will include dermatological examinations every 3 months,
(assessment of skin infections and general dermatological skin condition) and
keeping of a dosing- and UV-exposition diary by the patient.
4.3.1 Randomisation procedure
Patients who meet all of the inclusion criteria and none of the exclusion
criteria will be eligible for randomisation. Eligible patients will be
centrally randomised in a 2:1 ratio to one of the two treatment arms, either
MD-3511356 or standard sun protection measures. By the use of a randomisation
FAX within each centre each patient will receive a unique random. The trial
medication behind this random number is pre-determined by a computer-generated
randomisation procedure. Randomisation will be conducted on a competitive basis
across all trial centres.
4.3.2 Blinding procedure
Not applicable, as this will be an open-label trial.
4.4 Treatment, Trial Medication, Dosage, Application Form and Labelling
4.4.1 Application, period of application
In Group A the lotion MD-3511356 will be applied topically each morning on the
sun-exposed areas (face, neck, head, forearms and hands) in doses corresponding
to the surface extent. After application, patients need to wait for 2-3 minutes
to allow the lotion to dry. The dispensers will be provided with a dosage pump
to allow application of reproducible amounts (each pump 0.5 g). MD-3511356 will
be used once daily for 24 months.
Group B will use self-provided sunscreen products.
4.4.2 Investigational product
The investigational product supplied by the Sponsor will have been
manufactured, tested and released according to current GMP guidelines.
MD-3511356 is provided by Spirig Pharma AG. The comparator sun protection
products will be bought from a pharmacy or from drug stores by the patient
himself.
4.4.3 Packaging and labelling
The investigational medical device is signed for use in clinical trials only.
Each dispenser is labelled with the following information: patient random
number, Group A, protocol number, batch number, expiry date, name of the
sponsor, to store at room temperature, for clinical trial use only.
4.4.4 Storage
The medical device should be stored at room temperature.
4.5 Trial Period/Duration of Patient Participation
Before enrolment and treatment, patients at each trial centre will be
pre-screened for eligibility in the 1st quarter 2010. The following recruitment
period is expected to last 3 months. The duration of the trial for each patient
will last 24 months.
Patients* recruitment is planned to start in the 2nd quarter 2010
(First-patient-in) and is planned to end 3 months after recruitment start
(Last-patient-in). Recruitment is completed when the planned patient number is
achieved. Last-patient-out is scheduled for 3rd / 4th quarter 2012.
4.6 Accountability Procedures for the Investigational Medical Device
The number of dispensers used will be documented. The dispensers will be
weighted to determine the remaining amount of sun protection lotion in the
container.

6. TREATMENT OF PATIENTS

6.1 Administration and Treatment Period
Patients will be randomly assigned in a ratio of 2:1 to one of two treatment
arms:
Group A: Patients will receive detailed information on sun protection measures.
Additionally, they will be provided free of charge with MD-3511356 for
application to sun exposed skin areas once daily in the morning for 24 months.
Every morning MD-3511356 should be applied liberally to those skin areas
exposed to direct sunlight before exposing to the sun. It should be applied
before using the normal cosmetics (allow a few minutes for MD-3511356 to be
absorbed by the skin). Following longer periods in the water or after sweating
heavily reapplication is indicated.
Group B: Detailed information on standardised sun protection measures and
application of commercially available self-provided sunscreen products.

Not applicable