ARTICLE
Auteur(s) : Jean-Paul
Ortonne, Catherine Queille-Roussel, Luc Duteil
Centre de pharmacologie clinique appliquée à la dermatologie
(CPCAD), Hôpital de l’Archet 2, F-06202 Nice Cedex 3, France
accepté le 9 Mars 2006
Actinic keratosis (AK) is a pre-malignant skin lesion which is
predominantly caused by exposure to sunlight. The American Academy
of Dermatology estimates that 60% of predisposed individuals aged
40 years and over have at least one AK, making it the most common
form of pre-cancerous skin lesion [1]. AKs occur as intraepidermal
lesions primarily on surfaces exposed to sunlight, such as the face
and arms. The physical appearance may vary from 1-2 mm papules
to larger plaques, pigmented or erythematous with a rough
hyperkeratotic surface and occasionally horn formation
[1].Histologically and cytologically AK should be regarded as an
early stage of squamous cell carcinoma (SCC), with specific
ultraviolet (UV) induced mutations in the p53 gene present in 90%
of SCC in humans also being present in AK [2]. Early treatment is
therefore essential to prevent further progression [3-5]. The
incidence of AK is rising despite increased sun awareness in the
general population. The suggested reasons for this rise include
both increasing age and a greater than ever amount of leisure time
spent on outdoor pursuits. Currently, more than 100,000 patients
present with an AK every year in the UK alone [6]. Risk factors for
developing AK include a combination of fair skin and a high
cumulative lifetime exposure to UV radiation from sunlight or
artificial sources. Other predisposing factors include
immunosuppression and certain genetic conditions such as xeroderma
pigmentosum [1].Recent insights into the relationship between
cyclooxygenase 2 (COX-2) isoenzyme expression and carcinogenesis
has provided a rationale for the use of non-steroidal
anti-inflammatory drugs (NSAIDs) for the treatment of AK [7-11].
One of the most widely used and thoroughly documented topical
preparations is 3% diclofenac in 2.5% hyaluronic acid
(Solaraze™). 3% diclofenac in 2.5% hyaluronic acid has
been demonstrated in randomised clinical trials to significantly
reduce the number and severity of AK lesions over a treatment
period of 60 to 90 days, and has proven to be well tolerated
[12-15]. Medical treatment of AK sometimes occurs concurrently with
the daily use of sunscreens and many people are still exposed to
sunlight during treatment; based on this rationale two Phase IV
studies were carried out with the aim of assessing the
phototoxicity and photosensitisation potential of 3% diclofenac in
2.5% hyaluronic acid.
Materials and methods
Subjects
Healthy male and female individuals were eligible for inclusion in
either of the two studies provided they fulfilled the following
inclusion criteria: age 18 to 65 years; no signs of skin irritation
such as erythema, dryness, roughness or scaling on the areas to be
tested; females of childbearing potential must have used a reliable
contraceptive method for two months prior to the start of the study
and had to consent to continue using this for the duration of the
study and a period of one month after the end of the study, and
provide a negative urinary pregnancy test before enrolment.
Exclusion criteria included pregnancy or breastfeeding, or planned
pregnancy during the course of the study; skin with abnormal
pigmentation; skin type that could confound the interpretation of
treatment effects (skin type V and VI on the Fitzpatrick scale
[16]); any systemic or cutaneous condition that could confound the
interpretation of treatment effects; a history of active
photo-induced or photo-aggravated disease; exposure to excessive or
chronic UV radiation, such as sunbathing or phototherapy, within
four weeks prior to inclusion or planned during the study period;
any scars, moles, sunburns or other blemishes that could confound
grading; use of systemic medications that could affect the
inflammatory response, such as corticosteroids and other
anti-inflammatory drugs, within two weeks prior to inclusion; use
of systemic or topical medications suspected of causing
photobiological reactions, such as tetracycline or thiazides,
within one month prior to inclusion; known sensitivity to any of
the study treatments used.
Both studies were conducted in accordance with the Declaration
of Helsinki and its amendments, the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical
Practice (GCP), and local regulatory requirements. The study
protocols and all their amendments were reviewed and approved by an
independent ethics committee. All study participants provided
written informed consent prior to inclusion.
Irradiation material
The light source was produced by a solar simulator equipped with a
high-pressure xenon-vapour lamp which delivered a continuous
spectrum from 240 to 1100 nm (Solar simulator IDEM 3000,
Arquantiel, France). The simulated solar UV spectrum including UVB
and UVA was obtained using Schott WG320 and UG11 filters
combination as recommended by the COLIPA guidelines [17].
For the UVA irradiation, the UVB component of the spectrum was
eliminated by using a WG 335 (3 mm) filter. The infrared
filtration was reinforced with the UG11/1 mm filter placed in
a water filter. The lamp was switched on 15 minutes before the
first irradiation. A light intensity check was made prior to each
irradiation with a UV-meter SOLAR LIGHT (721 Oak lane Park, PA
19126, USA) with 2 photosensitive cells: one for UVA (320-400 nm)
and one for UVB (280-320 nm).
All types of irradiation (MED determination, UV and UVA
irradiations) were performed using the same solar simulator.
Study design
The two studies were both phase IV, single-centre, randomised,
controlled, investigator-blinded, intra-individual comparative
studies, designed to investigate in study A, the phototoxicity
potential and local tolerance, and in study B the
photosensitisation and sensitisation potential of 3% diclofenac in
2.5% hyaluronic acid (Solaraze™, Shire Pharmaceuticals
Group SA, France).
Both studies were designed to investigate 3% diclofenac in 2.5%
hyaluronic acid alone and in combination with two different
sunscreens (sunscreen1: Soltan 35, Boots plc, UK and sunscreen2:
Clinique Face SPF 30, Clinique Laboratories, Belgium). The
methodologies used to assess the phototoxicity and
photosensitisation potential were adapted from those described by
Kaidbey and Kligman [18, 19]. These are the methods usually
accepted by the FDA and other regulatory authorities for assessing
the phototoxic and photosensitisation potential of topical drugs.
The sensitisation potential was assessed using the same methodology
as the photosensitisation test with the only exception that the
skin areas tested were not irradiated.
During Day 1 and 2 of each study, the minimal erythema dose
(MED) for each participant was determined by exposing six
unprotected skin sites to incremental doses of UV irradiation. The
increment between doses followed a geometric progression of 1.25 as
recommended by COLIPA guidelines. The MED was determined at 22-24
hours post-irradiation, as the smallest dose of energy that
produced a perceptible redness that covered the entire exposed
area.
Study treatments were applied as six patches on either side of
the back, as shown in ( figure 1 ). One side of the
back was assigned to the irradiation procedure whilst the other
side was not irradiated, to allow distinguish between treatment
effects and irradiation effects.
Thirty subjects is a regulatory requirement for studies
investigating the phototoxicity and photosensitisation potential of
a chemical entity.
Study A: assessment of phototoxicity potential
On Day 1 of the study, three patches (12 mm diameter Finn
Chambers®) of 3% diclofenac in 2.5% hyaluronic acid and
three untreated control patches were applied on either sides of the
back as shown in ( figure 1 ). The products
were randomly applied (50 μL) to the patches and the investigator
and evaluator were blinded to the identification of all the test
areas as the application and removal was performed by a third
person. The patches were left under occlusion for 24 hours. The
patches were then removed, and after 30 minutes the two different
sunscreen products were applied at a concentration of 2
mg/cm2 on two out of the three areas treated with 3%
diclofenac in 2.5% hyaluronic acid and on two of the three control
areas. After a further 15 minutes, the left side of the back was
irradiated using UVA at 20 J/cm2 followed by UV at 0.75
MED. The right side of the back was not irradiated, in order to
assess local tolerance. Skin reactions on both sides of the back
were assessed at 60 minutes post-irradiation and then at 24, 48 and
72 hours.
Skin reactions on test areas were assessed using a six-point
scale: 0 - no erythema; 0.5 - equivocal erythema (barely
perceptible with no clearly defined border); 1 - mild but definite
erythema with clearly defined border (MED); 2 - moderate, clearly
defined erythema with or without oedema or papules; 3 - severe
erythema, oedema with or without papules; 4 - severe erythema,
oedema with vesicles or bullous reaction.
At the end of the study, any phototoxic reaction was evaluated
by comparing each irradiated patch to its non-irradiated equivalent
and scoring it as follows: 0 - negative; 1 - equivocal; 2 -
positive. All test areas were evaluated for phototoxic reactions at
24, 48 and 72 hours. Any other skin reactions, such as papules,
vesicles, blisters, dryness, cracking and peeling were noted
individually, as were adverse events.
Study B: assessment of photosensitisation potential
The photosensitisation study comprised three phases: a 3-week
induction phase, followed by a 2-week rest phase and a single
application challenge phase. The schedule for
application/irradiation and rest phase is dictated by the
photosensitisation reaction which is mediated by the immune system.
The induction phase is therefore followed by a rest phase in order
to allow any (photo)sensitisation reaction to eventually take place
during the challenge phase. Since any potential photoreaction
occurring upon challenge is also expected to be delayed; patch site
examination is therefore required up to 72 hours after irradiation.
During the induction phase, each participant’s MED was determined
as described above, and study treatments were applied to six
patches on either side of the back under occlusion for 24 hours in
the same way as for study A. The products were randomly applied to
the patches and the investigator and evaluator were blinded to the
identification of all the test areas as the application and removal
was performed by a third person. However, whilst the phototoxicity
study involved only one single exposure, in the photosensitisation
study the exposure was repeated twice-weekly for three weeks.
Thirty minutes after the removal of each patch, the left side of
the back was irradiated whilst the right side was not irradiated,
in order to assess any sensitisation reactions. During the first
week the UV dose was 2 MED, whilst during the second and third
weeks the dose was increased to 3 MED.
Skin reactions on both sides of the back were assessed at 30
minutes after the removal of the patches, prior to application of
sunscreens and irradiation. The reactions were assessed according
to a five-point scale: 0 - no erythema; 0.5 - doubtful erythema; 1
- mild erythema; 2 - moderate erythema; 3 - severe erythema. Any
other skin reactions were noted individually.
The induction phase was followed by a rest phase of two weeks
without any treatment application or irradiation. The subsequent
final part of the study consisted of a challenge phase, during
which study treatment was applied to six patches at new sites on
each side of the back as described above. The left side was then
irradiated with 0.75 MED UV, followed by 4 J/cm2 UVA,
whilst the right side was not irradiated, in order to assess any
sensitisation reactions.
Skin reactions on both sides of the back were assessed at 24, 48
and 72 hours post-irradiation, and were assessed according to a
global clinical score: 0 - normal skin aspect; 0.5 - equivocal
reaction; 1 - slight erythema with small papules and/or slight
oedema; 2 - moderate erythema with papules and/or vesicles and/or
oedema; 3 - intense erythema, oedema, confluent vesicles forming
blisters. The assessment of erythema was identical to the induction
phase. Any other skin reactions were noted individually.
At the end of the study, any photosensitisation reaction was
evaluated by comparing each irradiated patch to its non-irradiated
equivalent and scoring it as follows: 0 - negative; 1 - equivocal;
2 - positive. The occurrence of any sensitisation reaction was
assessed in the same way.
Results
Demographics
A total of 32 individuals (five males, 27 females) aged between 21
and 58 years were included in the phototoxicity study, and all
completed the study per protocol. The demographics and baseline
characteristics of the participants of this study are summarised in
table 1( Table 1 ). Eight concurrent
diagnoses were recorded as ongoing at the start of the study. The
majority of these were related to peripheral vascular disorders (n
= 6). None of the concurrent diagnoses were deemed to interfere
with the study assessments.
The photosensitisation study included 32 individuals (10 males,
22 females) aged between 23 and 57 years, of which 30 completed the
study per protocol. The demographics and baseline characteristics
of the participants of this study are also summarised in table 1.
One participant was withdrawn from the study at Day 7 due to use of
unauthorised medication (a corticosteroid-based anti-inflammatory
medication). A further participant withdrew from the study during
the rest phase due to a serious adverse event which was deemed
unrelated to the study treatment, namely hospitalisation for severe
depression. Thus results from the induction phase were analysed
based on the intention to treat (ITT) population (n = 32), and
results from the challenge phase were analysed using the per
protocol (PP) population (n = 30). In addition, a total of seven
concurrent diagnoses were recorded as ongoing at the start of the
study, the majority of which were related to peripheral vascular
disorder (n = 3) and known sensitivity to nickel. None of the
concurrent diagnoses were deemed to interfere with the study
assessments.
Table 1 Demographics and baseline characteristics for
the participants of the phototoxicity and the photosensitisation
study
|
Phototoxicity study
|
Photosensitisation study
|
|
N = 32
|
ITT N = 32
|
PP N = 30
|
|
Age (years)
|
Mean ± sd
|
38 ± 12
|
36 ± 10
|
36 ± 11
|
|
Min
|
21
|
23
|
23
|
|
Max
|
58
|
57
|
57
|
|
Gender
|
|
|
|
|
|
Male
|
n (%)
|
5 (16%)
|
10 (31%)
|
10 (33%)
|
|
Female
|
n (%)
|
27 (84%)
|
22 (69%)
|
20 (67%)
|
|
Skin type
|
II
|
2
|
2
|
2
|
|
III
|
29
|
30
|
28
|
|
IV
|
1
|
0
|
0
|
|
Weight (kg)
|
Mean ± sd
|
69 ± 9
|
62 ± 10
|
62 ± 10
|
|
Min
|
50
|
50
|
50
|
|
Max
|
89
|
88
|
88
|
|
Height (cm)
|
Mean ± sd
|
167 ± 7
|
167 ± 10
|
167 ± 10
|
|
Min
|
152
|
151
|
151
|
|
Max
|
183
|
192
|
192
|
|
MED (MED/min.sec)
|
Mean ± sd
|
183 ± 53
|
178 ± 41
|
176 ± 42
|
|
Min
|
99
|
109
|
109
|
|
Max
|
275
|
275
|
275
|
Phototoxicity
The assessment of erythema reactions at the test areas at 60
minutes following irradiation cannot be considered as assessment
for a phototoxic reaction as several phenomena may alter this
observation, such as residual thermal erythema. Moreover, one hour
represents generally too short a time to allow the observation of a
true phototoxicity reaction. At 24, 48 and 72 hours, only 6.9% of
erythema scores were higher than zero (mostly 0.5: equivocal
erythema) in the irradiated group. At 48 and 72 hours after
irradiation almost all test sites were scored zero on both
irradiated and non-irradiated areas. All of the scores different
from zero were between 0.5 and 1. From 24-72 hours, the lowest
proportion of reactions different from zero occurred on areas
treated with 3% diclofenac in 2.5% hyaluronic acid in combination
with sunscreen products, on both the irradiated (1.0%) and
non-irradiated side (2.1%). The highest proportion of reactions
different from zero was seen on the irradiated untreated (but
occluded) areas (19.8%).
The investigator’s assessment of a possible phototoxic reaction
at the end of the study (72 hours after irradiation), which
involved evaluation of the irradiated test areas compared with both
the corresponding non-irradiated areas and with untreated,
irradiated, control areas, showed that no phototoxic reactions
occurred on any of the treated areas during the study.
The other main local skin reaction one hour after irradiation
was immediate pigmentation of the skin, which occurred on areas
treated with 3% diclofenac in 2.5% hyaluronic acid (n = 28), 3%
diclofenac in 2.5% hyaluronic acid and sunscreen [Soltan] (n = 2)
or untreated areas (n = 31). From Day 3 onwards, ten areas treated
with either sunscreens or 3% diclofenac in 2.5% hyaluronic acid
combined with sunscreens showed residual pigmentation.
No local reactions were observed on the non-irradiated
areas.
Local tolerance
Assessment of test areas on the non-irradiated side of the back
showed very few ‘non-zero’ reactions. From Day 3 onwards, all test
areas, except the untreated (but occluded) area, scored zero;
untreated areas were scored between 0.5 and 1. Similar to the
phototoxicity evaluation, the lowest proportion of reactions
different from zero were seen on areas treated with combined 3%
diclofenac in 2.5% hyaluronic acid and sunscreen compared to other
areas.
Photosensitisation
The results of the photosensitisation analysis showed that the
overall proportion of patients with erythema reactions different
from zero was low. The lowest incidence of ‘non-zero’ reactions on
the irradiated side during the induction phase was seen in the
areas treated with combined 3% diclofenac in 2.5% hyaluronic acid
with sunscreens (3.2%) or 3% diclofenac in 2.5% hyaluronic acid
alone (10.3%) whereas the highest frequency of reactions was seen
on untreated but occluded areas (42.6%).
During the challenge phase, the number of reactions different
from zero for the erythema score was very low for all treatments on
the irradiated side: less than 3% of areas treated with 3%
diclofenac in 2.5% hyaluronic acid alone or in combination with
either sunscreen. The global clinical score was zero for all
treatments throughout the challenge phase.
Other local reactions observed during the study consisted mainly
of UV induced pigmentation on patches not treated with sunscreen.
During the induction phase, a total of 273 areas treated with 3%
diclofenac in 2.5% hyaluronic acid and 292 untreated areas showed
induced pigmentation, followed in the challenge phase by 37 and 50
areas, respectively and also one area treated with 3% diclofenac in
2.5% hyaluronic acid and sunscreen1 (Soltan).
Sensitisation
The sensitisation analysis on the non-irradiated side of the back
showed that no intolerance reaction or other local reaction was
observed for 3% diclofenac in 2.5% hyaluronic acid when applied
under occlusion, alone or in combination with sunscreen.
The investigator’s assessment of possible photosensitisation and
sensitisation reactions at the end of the study, comparing
irradiated test areas with both the corresponding non-irradiated
areas and with untreated irradiated control areas, showed that no
photosensitisation or sensitisation reaction occurred during this
study.
Adverse events
Adverse events were reported by a total of ten patients in the
phototoxicity study (11 events) and nine patients in the
photosensitisation study (12 events). In addition, one patient in
the photosensitisation study reported a serious adverse event,
namely severe depression requiring hospitalisation. None of these
adverse events were deemed to be likely to be related to the study
medication, or to interfere with the study analyses. The most
frequently reported adverse events in these studies included
headache (27% and 31%), and common cold (27% and 15%),
respectively.
Discussion
The two Phase IV studies show that no phototoxic,
photosensitisation or sensitisation reactions occur with 3%
diclofenac in 2.5% hyaluronic acid when applied alone or in
combination with sunscreen products. The measurements used, namely
visual assessments according to a grading scale, have been widely
used in the dermatology literature and are well accepted as a means
of evaluating sensitisation or irritation reactions. The
application of study treatments was randomised and the investigator
was blinded to the treatment to eliminate any bias. The method of
irradiating one side of the back whilst the other side is not
irradiated provided a means of distinguishing treatment reactions
from irradiation reactions.
In both the phototoxicity and photosensitisation analyses areas
treated with 3% diclofenac in 2.5% hyaluronic acid in combination
with sunscreens had the lowest incidence of erythema reactions,
indicating that 3% diclofenac in 2.5% hyaluronic acid is well
tolerated when used in conjunction with sunscreen products, and
with exposure to UV irradiation. This is explained by the
combination of the protective effect of sunscreens against UV light
skin penetration and the known anti-inflammatory activity of
diclofenac on the UV induced pain and erythema (sunburns) [20, 21].
On the other hand, the highest number of erythema reactions was
seen on the untreated (but occluded) irradiated and non-irradiated
areas in both studies. This is a well-known phenomenon observed on
untreated but occluded sites generally used as control for
tolerance studies [22-24]. In fact, the occlusion induces the
accumulation of sweat on the skin, which can be irritating over a
24-hour period. The untreated but occluded sites are often
classified as slightly irritant. The mechanical friction of the
patch on the skin surface, which is not lubricated by a cream or a
gel, may have an irritating character as well. On the irradiated
side for both types of studies, the irradiation effect is
superimposed to the patch induced effects. Concerning the
irradiation effect, in the phototoxicity method, the irradiation
dose (20 J/cm2 UVA + 0.75 MED) corresponds to a dose
that does not induce UV erythema (or only a weak one) but is high
enough to trigger a phototoxic reaction if the tested product does
have this potential. The irradiation dose of the challenge phase of
the photosensitisation test is even lower (4 J/cm2 + 0.5
MED) because this type of reaction is less dose-effect sensitive
than the phototoxicity reaction. Thus, the difference observed in
both types of study between untreated and treated sites was most
likely due to the combined effects of diclofenac and sunscreens
which suppress the UV and occlusion induced effects.
For both types of study, each treated and irradiated site had to
be compared to the following corresponding site:
- – the treated but non-irradiated site in order to allow
the distinction between photosensitisation reaction and
sensitisation reaction (or phototoxicity versus irritation);
- – the untreated but irradiated site to distinguish between
drug related photosensitisation reaction and non-drug related
photo-induced reaction (photo-sensitive subject);
- – the untreated and non-irradiated site as control for a
possible reaction to the occlusive patch itself (occlusion
effect).
Before concluding a phototoxicity or a photosensitisation
reaction, the investigator has to take into account these three
comparisons.
In addition to the erythema scoring, the global clinical score
measured in the photosensitisation study remained zero throughout
the study, further supporting the high tolerability of combined 3%
diclofenac in 2.5% hyaluronic acid and sunscreens.
Sun protection is a vital part of AK management [1]. Although it
is recommended that patients with AKs avoid exposure to direct
sunlight, this still often occurs for those in sunny climates.
These two studies demonstrate that 3% diclofenac in 2.5% hyaluronic
acid is safe to be applied in conjunction with sunscreens and that
exposure to sunlight does not result in phototoxic or
photosensitisation reactions. There have been rare examples of
contact dermatitis/ photosensitivity with 3% diclofenac in 2.5%
hyaluronic acid in the literature [25, 26] however this study
clearly demonstrates the potential risk for sensitisation or
photosensitisation reactions with 3% diclofenac in 2.5% hyaluronic
acid is extremely low. In addition, the studies confirm the
findings from randomised and open-label clinical trials, that 3%
diclofenac in 2.5% hyaluronic acid is a well-tolerated therapy with
a low incidence of adverse events, all of which are mild to
moderate in nature [12-15].
In summary, the two studies described here showed that no
phototoxicity or photosensitisation reactions occurred at any time
on any of the test sites exposed to 3% diclofenac in 2.5%
hyaluronic acid either alone or in combination with sunscreen
products. Neither did 3% diclofenac in 2.5% hyaluronic acid cause
any sensitisation reactions and the local tolerance was
satisfactory for all treatments tested.
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