International study in patients with acne · Bibliography 20 Annex I 22 - 29 Annex 1 – 5 30 - 38 Annex II – Tables + Graphs 39 - 55 Annex III - Photodocumetation 56 - 68 ... acne

International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris

(Cook’s acne severity grading scale 1-4)

Final Report

Study coordinator: Hana Zelenková, M.D., Ph.D.

Submitted by: Hana Zelenková, M D., Ph.D.

For: Catalysis, S.L., Madrid

Svidník, April 2006

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Contents: Contents 2

Introduction 3

Acne vulgaris. Its definition and therapy 4

Basic product information and characteristics 7

Study objective 8

Study characteristics, type and schedule 9

Participating countries, clinics 9

Material and methodology 10

Results 15

Discussion 16

Conclusion 19

Bibliography 20

Annex I 22 - 29

Annex 1 – 5 30 - 38

Annex II – Tables + Graphs 39 - 55

Annex III - Photodocumetation 56 - 68

Annex IV - Photodocumetation – summary 69 – 80

Annex V – CD 81

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Introduction

In 2005 (from 1 February 2005 to 30May 2005) a pilot study was carried out at the

Private Department of Dermatology DOST in Svidník to prove the efficacy and tolerability of

a preparation containing glycyrrhizinic acid in patients suffering from mild and

moderate acne vulgaris (grade 2 - 4 acc. to Cook’s acne severity grading scale). The study

was an open trial of type IV with post registration monitoring. The conclusions of this study

introduced quite surprising results demonstrating 77.77% efficacy of the preparation in a

group of 18 patients, whereby the tolerability of the preparation was excellent in all patients

included.

Taking into consideration that the trial was dealing with inventive therapeutic

employment of a preparation containing glycyrrhizinic acid resulting from practical

experience, and that there was no information described in literature on a similar group of

patients with the same diagnosis to compare the therapy, the company Catalysis S.L. Madrid

decided to carry out an extensive international multicentre study.

The study was defined as an:“ International, prospective, randomized, controlled

multicentre study to prove the efficacy and tolerability of a preparation containing

glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)“.

11 Clinics and departments from Slovakia and the Czech Republic (Study Design, see

Annex No I) participated in the study. The project monitoring was designed taking into

consideration the possibility to study clinical efficacy and safety of the preparation in question

and the possibilities of its employment in everyday practice.

For the purposes of this study, the preparation used and delivered to the clinics and

employed in practice was Granex®, a product of the company Catalysis, S.L., Madrid,

Spain.

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Acne vulgaris. Its definition and therapy.

Acne vulgaris – is one of the most common diseases, and as for its therapy, also one

of the conditions that are the hardest to influence therapeutically. The number of patients aged

12 – 25 affected by this disease is growing constantly. Dermatologists daily encounter a

number of cases of acne, from the mildest up to the most significantly complicated ones.

Apart from having to justify the therapy they choose and employ, they also have to answer the

questions asked by unhappy and dissatisfied patients concerning „the preparations that really

work“, which are continuously being introduced to the market by various cosmetic

companies. Pharmaceutical companies are not lagging behind them and also seek to produce a

variety of preparations to be used both topically and systemically. The approach adopted

towards acne therapy differs in various countries of Europe. For example, in Western Europe,

the patients first go to the drug-stores, chemists and pharmacies and the person that happens

to be their first advisor on the matter is the pharmacists, whereas in Eastern Europe young

people apply to dermatologists for advice from the beginning.

Within the past few years there have been significant changes in the approach towards

acne vulgaris therapy. Of course the therapeutic approach depends on the severity grade of

acne and the extent of the condition, with the sex of the patient playing a decisive role. In

order to design a targeted individual therapy plan, it is absolutely necessary to elaborate and

assess clear pathogenetic principles.

In acne vulgaris therapy, it is basically necessary to adhere to the following scheme:

mechanic cleansing, topical therapy (alcohol solutions containing 1-2% erythromycin or other

macrolide antibiotics, preparations containing salicylic acid, resorcinol, Ichthamol, azelaic

acid, retinoids and other), physical therapy (cryotherapy, dermabrasion, laser, laser scanner

etc.), systemic drug therapy (antibiotics, anti-androgens, isotretinoin, vaccines), individual

diet plan (the opinions adopted on this matter vary in different authors) and counselling.

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Acne vulgaris develops in puberty in 100% of teenagers in its either mildest and

transient or complicated forms causing scarring. Primarily during the period of hormonal

changes the activity of sebaceous glands increases accompanied by abnormal cornification of

the skin surrounding the opening of the hair follicles.

Table No 1 Primary, secondary and tertiary efflorescence in acne

normal sebaceous gland follicle follicle filament in a sebaceous gland follicle

microcomedo closed comedone open comedone

primary non-inflammatory efflorescence

papule pustule indurate node abscessed node abscessed fistula duct

secondary inflammatory efflorescence

fistula comedones cyst vermicular scar cyst scar closed comedo scar small node scar keloid scar atrophic scar

tertiary post-inflammatory efflorescence

The comedone mechanically restricts the excretion of excessive sebum or makes it

literally impossible. The pressure of the accumulated sebum around the hair follicle and

sebaceous gland acts like a foreign body and causes an inflammatory response. Sebum

decomposition may be caused or accelerated also by the colonisation of rapidly multiplying

microbial flora, most of all anaerobic Corynebacteria/cornybacteria (Corynebacterium acnes

I. and II., Corynebacterium granulosum, Propionibacterium acnes) and Staphylococcus

epidermidis, Staphylococcus pyogenes, yeasts – Pityrosporum ovale and others. Local

inflammation and other changes reflecting the intensity of the condition are specified in

various schemes.

According to Plewig, acne macroscopically most often develops into the following

forms:

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• Acne comedonica

• Acne papulopustulosa

• Acne conglobata

For the purposed of this study we used Cook’s acne severity grading scale.

Table No 2 Cook’s acne severity grading scale 0 - 8:

grade description

0 the skin does not have to be absolutely clear. Single comedones or papules may remain on the skin surface, however, visible only on closer inspection

2 on approximately 1/4 of the facial area small papules (6-12) and comedones may occur (small number of larger comedones or 20-30 small closed comedones). Isolated pustules or prominent papules are observed.

4 1/2 of the face is affected with small papules and large or small comedones. There are usually a few pustules or large papules present on the face. In case the lesions are quite extensive, the patient is graded with the grade "4", despite the fact that the area affected represents less than ½ of the whole face

6 on 3/4 of the facial area there are papules or large open comedones (less extensive areas of the face may also be affected, depending on the extent of inflammatory lesions). There usually are also numerous pustules of various sizes

8 disease lesions (of highly inflammatory type) present on the whole area of the face. Usually clearly visible large pustules. Other acne types such as acne conglobata, acne cystica or acne abscenens may also be present.

Note:

The acne severity grading scale 0 - 8 was designed as a linear scale, which means that the

difference between the grades 0 and 2 ought to be the same as the difference between the

grade 2 and 4, 4 and 6 etc. Grades 1, 3, 5, and 7 represent intermediary conditions

The scale is seen as a scale with an open end to assess extraordinarily severe acne

conditions. In exceptional cases patients may be diagnosed with acne graded 9 or 10.

In more serious forms of acne papulopostulosa it is inevitable to use topical therapy

combined with the employment of systemic antibiotics. The most frequently employed

antibiotics are tetracyclines and in case they are contraindicated, it is suitable to use

azithromycin, erythromycin or other macrolide antibiotics, chinolones or in exceptional cases,

metronidazol. Antibiotics are administered orally for weeks or even months. Following the

improvement of the condition, the initial loading dose is gradually decreased until finally

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replaced by the maintenance dose. The therapy effect is visible after approximately 4 weeks.

Isotretinoin is administered to patients suffering from severe acne forms. Other possibilities

include the employment of estrogens and anti-androgens administered in the form of oral

contraceptives to women, and the employment of the products STAVA and Polystafana.

In topical therapy new approaches are sought constantly and what has been evident

within the past few years is the comeback of preparations that had been used for centuries in

traditional medicine. Quite often a new therapeutic range is discovered of preparations that

had been applied only to a certain group of skin diseases. In this light it is very positive to

state that in topical therapy of mild and moderate acne forms (Cook 1-4) it is possible to

successfully employ a preparation containing glycyrrhizinic acid called Granex®, produced

by the company Catalysis, S.L., Madrid.

Basic preparation information:

Granex® represents a unique preparation produced by the company Catalysis, S.L.,

Madrid, Spain

Product description: The main active agent contained in the preparation Granex®, Catalysis, S.L., Madrid, Spain is

a water extract of glycyrrhizinic acid Glycyrrhizin, GL) 0,1g in 100g of vehicle and 5% of

Aloe Vera..

Glycyrrhiza glabra – especially its root– radix liquiritiae – radix glycyrrhizae glabrae -

has been widely used in pharmacy. Glycyrrhizinic acid (Glycyrrhizin, GL) is a substance of

glycosidic character. Aglycon is represented by glycyrrhetinic acid (glycyrrhetin).

The pentacyclic triterpene acid glucuronide is of steroid character. The sugar component is

represented by two molecules of glucuronic acid. The following split of the sugar component

results in the loss of sweetness.

One of the basic properties of Glycyrrhizinic acid is the water foaming property and its

low haemolytic efficacy. Glycyrrhizinic acid causes the inhibition of prostaglandin E2 in the

affected tissue and stops the replication of viruses as the result of virus P Kinase activity

inhibition. The induction of interpherone formation results in the activation of macrophages

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and potentiation of their phagocytary and bactericidal property. Interpherones exhibit antiviral

and antiproliferative effect.. Laboratory experiments in vitro have proven its inhibitory effect.

Animal testing has proven the zero mortality index as well as the minimal ocular and dermal

irritation.

Numerous clinical trials of Granex®, Catalysis, S.L., Madrid, Spain, performed at

departments of dermatovenerology and gynaecology have proven its excellent properties,

such as the ability to heal viral as well as bacterial infections. Granex®, Catalysis, S.L.,

Madrid, Spain, was without any problems administered also to pregnant women. Excellent

effects following the application of the preparation in the initial stage of infections have been

described.

TThhee eeffffeeccttss ooff ggllyyccyyrrrrhhiizziinn aarree aass ffoolllloowwss::

• anti-ulcerous

• anti-inflammatory

•• rreedduucciinngg tthhee nnuummbbeerr ooff ccoommeeddoonneess

• antiviral (exhibiting the ability to inhibit virus DNA and RNA) – varicella zoster,

HIV, influenza A,B, herpes simplex, hepatitis, HPV

Aloe Vera is a nutrient containing vitamin B1, B2, B6, C, niacin amide, choline and

18 amino acids, as well as many other active substances. The extract of Aloe Vera has been

used in many kinds of cosmetic products (creams, lotions, shampoos). In the preparation

Granex®, Catalysis, S.L., Madrid, Spain, Aloe Vera is used as an auxiliary substance

Granex®, Catalysis, S.L., Madrid, Spain is distributed in form of a set consisting of

200 ml of cleansing lotion and a 50 ml spray packed in a box.

Granex®, Catalysis, S.L., Madrid, Spain – other properties:

∗ neutral fragrance

∗ no risk of stains in case the preparation gets into contact with clothing

∗ the preparation can be applied without any problems during pregnancy and lactation

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Study objectives Application of a set of preparations including Granex®, lotion and spray developed by

Catalysis, S.L., Madrid, Spain within the performed study was supposed to prove the

following effects:

• significant reduction in the development of comedones and inflammatory lesions

• reduction in sebum production by more than 20%

• permanent reduction in the development of comedones

• in comparison with other orally administered tetracycline antibiotics, it is necessary to

accentuate the advantages of Granex®, Catalysis, S.L., Madrid, Spain such the elimination

of the risk of systemic adverse effects development (diarrhoea, vaginal candida infections,

photosensitivity)

Study characteristics, type and schedule International, prospective, randomized, controlled multicentre study

Study type: open trial of type IV, with post-registration monitoring.

Study schedule: January 2006 - selection and exclusion of the patients

February – April 2006 – carrying out the study May 2006 – assessment and processing of the results

June – December 2006 – presentation and publishing of

the results of the study

Participating countries and towns:

1. Slovak Republic – Svidník, Žilina, Bratislava

2. Czech Republic – Praha, Brno, Otrokovice

Clinics and departments: (The Slovak and Czech Republics)

Slovak Republic clinic/department Clinic No Svidník I – Hana Zelenková, M.D., Ph.D. 1 Svidník II – Júlia Stracenská, M.D. 2 Žilina I – Alena Nejdková, M.D. 3 Žilina II – Bohdan Hollý, M.D. 4 Bratislava – Eva Škutilová, M.D. 5 Czech Republic Brno I – Advisor doc. Jarmila Rulcová, M.D., Ph.D. 6

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Brno II – Zuzana Vykutilová, M.D. 7 Brno III – Sandra Vykutilová, M.D. 8 Praha I – Jiřina Cabalová, M.D. 9 Praha II – Jiřina Cabalová, M.D. 10 Otrokovice – Anna Raková, M.D. 11

Material and methodology

Prior to the commencement of the trial all participants at all clinics and departments

were given instructions and information on the design of the study, the processing of

documentation and photodocumentation as well as other relevant issues by the main study

coordinator.

Every participant was provided with the basic set of documents:

• Basic Working Protocol (Annex 1)

• Inclusion and Exclusion Criteria (Annex 2)

• Working and Evaluation Sheet (Annex 3)

• Number of patients (Annex 4)

• Patient Consent Form (Annex 5)

Number of patients in each clinic: 10

Documentation: Working Protocol, tables

Photodocumentation: pictures taken 2 - 4 times

Basic laboratory screening: performed in every single patient

Therapeutic effect assessment made: scale l - 5 (1 - healing, 2 - significant

by the therapist improvement, 3 - improvement,

4 - no improvement, 5 - aggravation)

Evaluation made by the patient: scale 1 – 5 (1 - excellent, 2 – very good, 3 -

good, 4 –without any changes, 5 – aggravation,

irritation)

Information on preparation application shall be provided by the therapist upon inclusion

into the study prior to the application

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Result processing: single clinics represented by the national coordinators shall provide the

main coordinator of the study with results for further processing or

publishing

(Working Protocols can be accessed through the main study coordinator)

Every patient was entered into a special protocol upon inclusion into the study. Apart

from basic data concerning the patient (name, surname, date of birth, habitus etc.) the protocol

included basic laboratory screening results, examination of focal infection or a microbiologic

examination – swabs taken from the pustules (the last three groups of parameters were not

subject of the clinical study, which is why they are not separately assessed in the Report),

local finding at the inclusion and after certain time intervals, efficacy of therapy,

photodocumentation, adverse effects and final assessment made by the therapist as well as the

patients themselves.

The monitoring of patients as such was performed at single clinics and

departments during the period from 1 February 2006 to 30 April 2006. 110 patients were

included into the series ( (37 (33,64%) male, 73 (66,36% female), their mean age being 18,13

years men, 20,16 women (whereby the youngest patient was a 12 year-old boy and the oldest

a woman aged 46).

Monitored diagnosis: Acne vulgaris – papulopustulosa (Cook 0-4)

Local finding assessment: was performed prior to inclusion into the study and after 4 and 8

weeks of therapy according to Cook’s acne severity grading scale 0 – 8 (Tab. No 2). The

assessment reflects the impression the patient makes on a strange person within the distance

of, 1 - 2 m. The morphs counted included open comedones, closed comedones, papules and

pustules.

The guidelines for study of Granex®, Catalysis, S.L., Madrid, Spain, recommended inclusion

of patients with acne severity grade 1-4, only. Any exceptions made had to be justified.

Protocol: recorded monitored morphs typical of acne vulgaris

Assessment of facial manifestations and the grading of the severity of the disease (entered

into a table ):

number of non-inflammatory lesions: on the right/on the left

∗ open comedones

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∗ closed comedones

∗number of inflammatory lesions: on the right/on the left

∗ papules

Tab. No 4 Assessment of facial manifestations

Monitored morphs Status localis at therapy commencement

Status localis after 2 weeks




open comedones (on the right/on the left)

closed comedones (on the right/on the left)

papules

(on the right/on the

left)

pustules


left)

nodules


left)

∗ Note: Neither pustules nor nodules ought to be present in patients included into the study

of the preparation Granex

Tab. No 5 Status localis after therapy termination graded according to Cook’s scale open comedones (on the right/on the left)



pustules (on the right/on the left)

nodules (on the right/on the left)

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Granex®, Catalysis, S.L., Madrid, Spain - application The product used was a topical preparation Granex®, produced by the company

Catalysis, S.L., Madrid, Spain.

Every clinic was provided with 10 sets of Granex®, (consisting of lotion and spray).

There was a possibility to obtain more samples upon request.

The patients were applying the preparation to predefined areas such as the cheeks, the

forehead and the nose. To sum it up, the whole facial area was treated in all patients.

Granex® – application instructions

∗ Granex ® is applied 3 times and day during the first 10 days and after that 2 times a

day on the whole facial area:

1. the face was cleansed with Granex ® lotion

2. which was followed by the application of Granex ® spray

∗ the preparation is to be used continuously until the resolution of the symptoms and

significant improvement of the condition of inflammatory lesions as well as reduction in the

number of comedones

• the preparation is applied for the minimum of 4 weeks (and the maximum of 6 weeks

or until significant improvement of the condition of inflammatory lesions and

reduction in the development of comedones, which needs to be marked)

• the evaluation of facial skin lesions is performed (at the inclusion into the group of

patients and after 2, 4 and 8 weeks

• the patients are followed-up for 4 weeks following the termination of the application

of Granex in order to verify the continuous improvement of the clinical picture of acne

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Inclusion and exclusion criteria:

Inclusion criteria:

- activation of the basic condition, insignificant manifestations of a bacterial infection

(pustules,)

- absence of oral therapy with antibiotics, chemotherapeutics or retinoids one month prior

to inclusion into the study

Exclusion:

- known hypersensitivity to any of the product’s ingredients

- pregnancy

- lactation

- other serious skin diseases

Warning:

The patients were at the same time using indifferent topical such as thermal water to

wash their faces. The preparations forbidden to use included other anti-acne preparations,

(salicyl-bor-resorcin alcohol, Acnemycin sol, paste, Acnefug EL, Dalacin sol, Eryfluid,

Acneroxid, Acnecolor and others). During the course of the therapy with Granex, neither

physical treatment nor chemical peeling was applied.

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Results

All basic data are to be inspected in Tables 1-4 and Graphs 1-21 annexed thereto.

Classification according to Cook’s acne severity grading scale:Grade 0-2. - 9 (8,18%)

patients, Grade 3. - 19 (17,27%) patients, Grade 4. - 82 (74,55%) patients. The mean disease

duration period counted 16 months (with the shortest period of 4 months and the longest of 9

years). The mean duration of the present episode counted 4.2 months .

Assessment of facial manifestations: the number of non-inflammatory lesions was

counted at inclusion into the series of patients and after 2 weeks. In 75 (68,18%) patients

there was a 75% reduction in that number. The number of inflammatory lesions was reduced

by 2/3 after 8 days, and in 79 (72,48%) patients there was full clearing of all inflammatory

manifestations towards the end of the monitoring period, 24 (22,02%) patient stage very

improved.

Laboratory screening was performed at inclusion into the study 96 patients, whereby

all monitored parameters were within the normal range. In 12 patients there was a slightly

elevated ASLO level and hypercholesterolemia was detected in 2 patients. The laboratory

screening performed at the end of the monitoring period in 100 patients revealed that all

monitored parameters were within the normal range, there was elevated ASLO level in 8

patients and hypercholesterolemia in 2 patients.

Presence of focal infection - otorhinolaryngology: infection proven in 12 patients (9

women, 3 men). Microbiologic examination of the pustules demonstrated 9 cases of

Staphylococcus epidermidis, 5 cases of Staphylococcus aureus, 1 case of Staphylococcus

pyogenes, (Note: u 2 patients there was mixed flora), and 1 case of Corynebacterium.

The tolerability of Granex®, Catalysis, S.L., Madrid, Spain was excellent or very

good in 109 patients. One patient discontinued the therapy.

Adverse effects of Granex®, Catalysis, S.L., Madrid, Spain (however, not

representing a reason to discontinue the therapy) were observed in 22 patients and included

slight erythema, scaling and development of open comedones at the beginning of therapy. In

one female patient the application of Granex® caused an allergic reaction (verified via testing

later on).

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The success of therapy with Granex®, Catalysis, S.L., Madrid, Spain was assesses

as very good in 100 (90.91%) patients and considered good in 9 (9,09%) patients by all the

therapists. In one patient the therapy showed no effect and caused slight aggravation resulting

in therapy discontinuation. In patients with significant sebum overproduction the effect was

observed to be less outstanding.

Patient satisfaction: 95 (87,16%) patients were very satisfied with the therapy due

to the rapid effect onset and the comfort of application, 14 (12,84%) patients considered the

therapy satisfactory, or effect indifferent and one female patient discontinued the therapy. The

therapy success is photodocumented. What the patients assessed most positively were the

quality and the application properties of Granex® spray, which, according to their words is

the only product on the market that neither dries out nor irritates the skin and makes it feel

fine and smooth.

Discussion

Based on the clinical condition of the patients as well as the achieved therapeutic

results, the efficacy and tolerability as well as the occurrence of adverse effects of the product

Granex®, Catalysis, S.L., Madrid, Spain were assessed.

Clinical finding: The results obtained are remarkable mainly in Table 4. At inclusion

examination there were 9 (8,18%) patients suffering from acne of grade 0 – 2 and grade 3.-4.

was observed in 101 (91,82%) patients. The assessment performed the termination of

application (Tab.No. 3,4) revealed that there were 103 (94,5%) patients with grade 0 – 2, and

6 (5,5%) patients with grade 3. Compared with the situation at the inclusion into the study, the

assessed facial manifestations (according to Cook’s acne severity grading scale) there was

healing or significant improvement in 79 (72,48%) patients and improvement in 24 (22,02%)

patients. There was slight improvement in 6 (5,50%) patients. In one patient there was

aggravation of the local finding due to allergy. As for the manifestations of the disease, six

patients were suffering from acne of severity grade 5-6 and in order to achieve satisfactory

results the employment of systemic therapy would be necessary. Systemic therapy was

commenced in those patients upon their exclusion from the study due to its termination, and

what needs to be stated is that improvement of the local finding was achieved. What was

really interesting in this light was the fact that those patients required to be treated with

Granex®, Catalysis, S.L., Madrid, Spain even after the termination of the study.

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In 79 patients there was extensive clearance of inflammatory lesions (72,48%) and in 24

patients (22,02%) there was significant reduction in the manifestations with only small

residues left.. In order to achieve total clearance of inflammatory as well as non-

inflammatory morphs, the application duration of Granex®, Catalysis, S.L., Madrid, Spain

would have to be prolonged to at least 3 months.

In 6 patients with significant sebum overproduction the effect was less significant and

as has already been mentioned above, systemic agents would have to be employed to achieve

better results. On the average, there was reduction in the number of inflammatory lesions by

more than 3/4.

Since the patients were undergoing topical therapy with Granex®, Catalysis, S.L.,

Madrid, Spain, only, we attribute the betterment of the disease to the application of this

product. Control swabs taken from residual foci of papulopustules and pustules only showed

Staphylococcus epidermidis in one case. In the rest of the patients there was no colonisation.

The therapy was well tolerated by the patients and the adverse effects were only of

transient nature (slight erythema, burning sensation, skin scaling) and did not represent a

reason for the therapy to be discontinued, which also was stated by the patients themselves.

Only in one case a female patient discontinued the therapy and was excluded from the series.

One of the every positive characteristics of the preparation employed is the fact that

there was significant improvement of the quality of skin visible nearly in all patients within a

very short period of time. Within 10 days there was improvement in the relief of the skin

(which is the proof of the fact that glycyrrhizinic acid and aloe vera exhibit a very soothing

effect and eliminate skin irritation). In this light the preparation seems excellent for the use in

patients with acne papulopustulosa according to Plewig – since there really is clearing of the

manifestations of the disease.

Excellent effects were observed (in all trial centres) especially in patients with

atopic constitution. It would be of benefit to take advantage of this observation in the

future, especially as regards the possible use of the preparations containing

glycyrrhizinic acid and aloe vera in main or topical supplementary therapy of eczema

atopicum.

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At all clinics and departments and in all patients there was rapid improvement and

significant reduction in primary non-inflammatory efflorescence, especially the closed

comedones. At the beginning of therapy the development of open comedones was slightly

increased in some patients, however, followed by significant improvement of the condition

and healing of the morphs.

After a month of therapy (4 weeks) there were some residual foci left on the faces of

some patients, which did not change significantly after 8 weeks ( Tab. No 3 with slight

disease activation in 22 patients, 20,18 %)

Ideally, in order to achieve total clearance of both inflammatory and non-inflammatory

morphs all the participating therapists recommend the preparation be used for 3 months

(which has been mentioned above).

The therapists also univocally claim that Granex®, Catalysis, S.L., Madrid, Spain

represents a unique supplementary topical preparation that can be used in more serious acne

conditions requiring the employment of systemic therapy with antibiotics or retinoids. This

was also supported by the expert consultant doc. MUDr. Jarmila Rulcová, Ph.D.

Granex®, Catalysis, S.L., Madrid, Spain was optimally applied as follows:

following the success obtained by employing the initial therapeutic dose (with the preparation

applied 3 times a day) it was recommended to use the product 2 times a day, only (in the

morning and in the evening). The difference in the duration of application within single

clinics and departments is a result of the different amount of preparation used as well as the

extent of the areas treated by the patients. Patients that were applying the preparation to less

extensive areas were using smaller amounts of the preparation and were thus able to use it for

a longer period of time.

Nearly all of the patients stated that the therapy was comfortable, not time consuming

and brought about a very pleasing cosmetic effect. Many of them underwent unsuccessful

long-term therapies with other preparations , based on which they considered the treatment

with Granex®, Catalysis, S.L., Madrid, Spain very successful and required to be treated

with the product in question even after therapy termination. The only thing they together with

the therapists considered a disadvantage of the set was the disproportion between its two

components. It should be recommended that the content of Granex® Spray be adjusted (to the

200ml content of Granex® lotion).

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Conclusion

The study performed has proven the declared positive therapeutic efficacy and

tolerability of the preparation Granex®, Catalysis, S.L., Madrid, Spain employed in topical

therapy of mild up to moderate forms of acne vulgaris. The results in full extent prove the

results of the pilot study carried out in 2005 and in comparison with the results of the pilot

study represent data more valid due to the number of patients included.

Taking into consideration the number of patients as well as the fact that 11 clinics

participated in the study (clinics, departments of dermatology in cities, towns and villages),

we presume that the efficacy of therapy of 93% may be considered extraordinarily

satisfactory.

Granex®, Catalysis, S.L., Madrid, Spain represents a modern preparation taking

advantage of the experience of traditional medicine. As for the therapy of acne vulgaris, it

represents a new and effective alternative form of treatment for an extensive group of the

persons affected by moderate acne forms (Cook’s grading scale 0-4). It is possible to

recommend the preparation be employed as supplementary topical therapy in patients with

severe acne papulopustulosa treated systemically with antibiotics or retinoids. The application

form of lotion and spray is well tolerated, causes minimal irritation of transient nature in

exceptional cases, but no adverse effects. The allergic reaction present in one female patient is

considered an exception.

It is possible to apply the preparation concomitantly with other systemically

administered agents and support the effect by employing mechanical or physical treatment

possibilities.

Excellent effects were observed especially in patients with atopic constitution. It

would be of benefit to take advantage of this observation in the future, especially as

regards the possible use of the preparations containing glycyrrhizinic acid and aloe vera

in main or topical supplementary therapy of eczema atopicum.

An experienced dermatologist can take advantage of this preparation to treat other

unpleasant indications such as acne vulgaris, which often is a disease bringing about serious

mental distress.

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Bibliography:

1. Fadrhoncová, A.: Farmakoterapie kožních nemocí (Pharmacotherapy of skin

diseases). Grada Publishing 1999, p.297 – 302.

2. Hegyi, E., Stodola, I., Hegyi, V.: Moderná terapia dermatovenerologických chorôb

v lekárskej praxi. (Modern therapy of dermatovenereal diseases in medical practice)

HEGPROF, Bratislava 1993, p.269 – 273.

3. Jautová, J., Jarčušková, D., Ficová, M., Dubivská, M.: Imunomodulačný

a terapeutický efekt prírpavku STAVA inj. u acne vulgaris. (Immunomodulatory and

therapeutic effect of the preparation STAVA inj. in acne vulgaris) Epidemiol.

Mikrobiol. Imunol., 44, 1995, 1, p. 29 – 32 .

4. Jarčušková, J., Jarčušková, D., Benečová, K.: Terapeutický prístup ku kombinovanej

forme acne tetrada – rhinophyma. (Therapeutic approach to the combined form of

acne tetrada – rhinophyma) Prakt. Lék., 75, 1995, č.5, p. 219 – 220.

5. Jautová, J., Jarčušková, D., Benečová, K., Dubivská, M., Petrovičová,J.:

Imunomodulačný a klinický efekt prípravku polystafana inj. u patientov s acne

vulgaris. Klinická imunológia a alergológia, (Immunomodulatory and clinical effect of

the preparation polystafana inj. In patients with acne vulgaris. Clinical immunology

and allergology) 6, 1996, č.4, p. 26 – 30.

6. Kolibášová, K., Hegyi, V., Hegyi, E.: Ošetrovanie a liečenie kožných a pohlavných

chorôb. (Treatment and therapy of skin and venereal diseases) HEGPROF, Bratislava ,

1994, p.304 – 307.

7. Korting, H. Ch., Arenberger, P.: Dermatologická terapie. (Dermatologic therapy)

Praha 1998, p. 119 – 121.

8. Lamp, K.C., Bailey, E.M, Rybak, M.J.: Ofloxacin Clinical Pharmacokinetics.

Clin.Pharmacokinet., 22, 1992, č.1, p. 32 – 46.

9. Lewin, C.S., Smith, J.T.: Bactericidal mechanism of ofloxacin. Journal of

Antimicrobial Chemotherapy 22 (Suppl. No 1, 1988, p.1 – 3.)

10. Litt,Z.J., Pawlak, A.W. Jr.: DERM 1997, The Parthenon Publishing Group, New York

– London 1997, p.313 – 314.

11. Doll, R., Hill, I.D., Hutton, C., Underwood, D. L.: Antiviral activity of glycirrhizic

acid. Lancet, 11, 1979, p. 793-796.

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12. Ohtsuki, K., Iahida, H.: Inhibitory effect of glycirrhizin on polypeptide phosporylation

by polypeptide-dependent protein kinase (Kinase P) in vitro. Biochemical and

Biological research communications. 1988; Vol. 157, No 2, p. 597 – 604.

13. Zelenková, H.: The use of preparations containing glycyrrhizinic acid in dermatology

practice. Congress of the Yugoslav Association of Dermatology and Venerology,

Beograd, 10.11.2002.

14. Zelenková, H.: Clinical study of GRANEX® in the treatment of acne vulgaris. Pilot

study performed for the company Catalysis, 2005, Madrid

15. Zelenková, H., Stracenská, J.: Zastosowanie preparatóv zawierajacych kwas

lukrecjowy w prakttyce dermatologicznej – leczenie tradzika zwyklego.

V.jubileuszowa Konferencija Stowarzysenia Lekarzy Dermatolog´w Estetycznych.

(The use of preparations containing glycyrrhizinic acid in dermatology practice to

treat acne vulgaris. Congress of the Association of Aesthetic dermatology. 31.3.-

2.4.2006, Warszawa, Abstracts p. 19.

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Annex I

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Study Design

International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with

acne vulgaris (Cook’s acne severity grading scale 1-4)

The Monitoring Project of Granex®, produced by the company Catalysis, S.L., Madrid, Spain, was designed to monitor clinical efficacy and safety of the preparation and the

possibility of its wide use in everyday practice

Main Study Coordinator: MUDr. Hana Zelenková, M.D., Ph.D., DOST Svidník Study type: IV, with post-registration monitoring and continuous

inclusion of patients into the study according to the set criteria and age

Study schedule: January 2006 - selection and exclusion of the patients

February – April 2006 – carrying out the study May 2006 – assessment and processing of the results

June – December 2006 – presentation and publishing of the results of the study

Participating countries and towns:

1. Slovak Republic – Svidník, Žilina, Bratislava 2. Czech Republic – Praha, Brno, Otrokovice

Clinics: (The Slovak and Czech Republics):

Slovak Republic Clinic Clinic No Svidník I – Hana Zelenková, M.D., Ph.D. 1 Svidník II – Júlia Stracenská, M.D. 2 Žilina I – Alena Nejdková, M.D. 3 Žilina II – Bohdan Hollý, M.D. 4 Bratislava – Eva Škutilová, M.D. 5 Czech Republic Brno I – Advisor doc. Jarmila Rulcová, M.D.,Ph.D. 6 Brno II – Zuzana Vykutilová, M.D. 7 Brno III – Sandra Vykutilová, M.D. 8 Praha I – Jiřina Cabalová, M.D. 9 Praha II – Jiřina Cabalová, M.D. 10 Otrokovice – Anna Raková, M.D. 11

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Number of patients in each clinic: 10

Documentation: Working Protocol, tables Photodocumentation: pictures taken 2 - 4 times Basic laboratory screening: performed in every single patient Therapeutic effect assessment: scale l - 5 (1- healing, 2 - significant improvement,

3 - improvement, 4 - no improvement, 5 - aggravation) Evaluation made by the patient: scale 1 – 5 (1- excellent, 2 – very good, 3 - good,

4 –without any changes, 5 – aggravation, irritation) Information on preparation application shall be provided by the therapist Result processing: single clinics represented by the national coordinators

shall provide the main coordinator of the study with results for further processing or publishing

Standard inclusion of patients was performed according to Cook’s acne severity grading scale

(Annex). At the end, by comparison and assessment exact efficacy of Granex®, Catalysis,

S.L., Madrid, Spain shall be determined

Cook’s acne severity grading scale 0 - 8 (the assessment reflects the impression the patient

makes on an unknown person from the distance of 1 - 2 metres)

Tab. No 2 Cook’s acne severity grading scale 0 - 8:

Grade Description

0 the skin does not have to be absolutely clear. Single comedones or papules may remain on the skin surface, however, visible only on closer inspection

2 on approximately 1/4 of the facial area small papules (6-12) and comedones may occur (small number of larger comedones or 20-30 small closed comedones). Isolated pustules or prominent papules are observed.

4 1/2 of the face is affected with small papules and large or small comedones. There are usually a few pustules or large papules present on the face. In case the lesions are quite extensive, the patient is graded with the grade "4", despite the fact that the area affected represents less than ½ of the whole face

6 on 3/4 of the facial area there are papules or large open comedones (less extensive areas of the face may also be affected, depending on the extent of inflammatory lesions). There usually are also numerous pustules of various sizes

8 disease lesions (of highly inflammatory type) present on the whole area of the face. Usually clearly visible large pustules. Other acne types such as acne conglobata, acne cystica or acne abscenens may also be present.

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A. the acne severity grading scale 0 - 8 was designed as and linear scale, which means

that the difference between the grades 0 and 2 ought to be the same as the difference between the grade 2 and 4, 4 and 6 etc. Grades 1, 3, 5, and 7 represent intermediary conditions

B the scale is seen as a scale with an open end to assess extraordinarily severe acne

conditions. In exceptional cases patients may be diagnosed with acne graded 9 or 10.

Within the study of the preparation Granex®, produced by the company Catalysis, S.L.,

Madrid, Spain, it is necessary to include patients that fall within the Cook’s scale grades

1-4.

The following morphs typical of acne vulgaris shall be monitored: ∗open comedones ∗closed comedones ∗papules ∗pustules • nodules

• Note: Neither pustules nor nodules ought to be present in patients included into the study of the preparation Granex

Evaluation of facial symptoms and general acne severity grade (to be inserted into the table): ∗number of non-inflammatory lesions: on the right/ on the left ∗open comedones ∗closed comedones ∗Number of inflammatory lesions: on the right/ on the left ∗Papules

Granex®, Catalysis, S.L., Madrid, Spain – application instructions ∗ Granex ® is applied 3 times and day during the first 10 days and after that 2 times a day on the whole facial area or other affected areas: the face is cleansed with Granex ® lotion which is followed by the application of Granex ® spray

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the preparation is used continuously until the resolution of the symptoms and

significant improvement of the condition of inflammatory lesions as well as reduction in the

number of comedones

• the preparation is applied for the minimum of 4 weeks (and the maximum of 6 weeks)

• the evaluation of facial skin lesions (at the inclusion into the group of patients and after 2, 4 and 8 weeks

the patients are followed-up for 4 weeks following the termination of the application of

Granex in order to verify the continuous improvement of the clinical picture of acne

Status localis: the monitoring of morphs and evaluation of facial symptoms as well as the

overall grade of the disease’s severity, whereby the number of non-inflammatory lesions on

the right and on the left side of the area (open comedones, closed comedones) and the number

of inflammatory lesions on the right and on the left side (papules) are assessed

Every clinic shall be provided with 10 sets of Granex®, Catalysis, S.L., Madrid, Spain (lotion and spray) and 10 sets of placebo preparation. More preparation samples may be sent upon request. .

Results must not be published without prior written consent of the company Catalysis,

S.L., Madrid, Spain

Basic preparation information:

Granex® represents a unique preparation produced by the company Catalysis, S.L.,

Madrid, Spain

Product description: The main active agent contained in the preparation Granex®, Catalysis, S.L., Madrid, Spain is

a water extract of glycyrrhizinic acid Glycyrrhizin, GL) 0,1g in 100g of vehicle and 5% of

Aloe Vera.

Glycyrrhiza glabra – especially its root– radix liquiritiae – radix glycyrrhizae glabrae -

has been widely used in pharmacy. Glycyrrhizinic acid (Glycyrrhizin, GL) is a substance of

glycosidic character. Aglycon is represented by glycyrrhetinic acid (glycyrrhetin).

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The pentacyclic triterpene acid glucuronide is of steroid character. The sugar component

is represented by two molecules of glucuronic acid. The following split of the sugar

component results in the loss of sweetness.

One of the basic properties of Glycyrrhizinic acid is the water foaming property and its

low haemolytic efficacy. Glycyrrhizinic acid causes the inhibition of prostaglandin E2 in the

affected tissue and stops the replication of viruses as the result of virus P Kinase activity

inhibition. The induction of interpherone formation results in the activation of macrophages

and potentiation of their phagocytary and bactericidal property. Interpherones exhibit antiviral

and antiproliferative effect.

TThhee eeffffeeccttss ooff ggllyyccyyrrrrhhiizziinn aarree aass ffoolllloowwss::

• antiulcerous

• anti-inflammatory

•• rreedduucciinngg tthhee nnuummbbeerr ooff ccoommeeddoonneess

• antiviral (exhibiting the ability to inhibit virus DNA and RNA) – varicella zoster,

HIV, influenza A,B, herpes simplex, hepatitis, HPV

Laboratory experiments in vitro have proven its inhibitory effect. Animal testing has

proven the zero mortality index as well as the minimal ocular and dermal irritation..

Aloe Vera is a nutrient containing vitamin B1, B2, B6, C, niacin amide, choline and 18

amino acids, as well as many other active substances. The extract of Aloe Vera has been used

in many kinds of cosmetic products (creams, lotions, shampoos). In the preparation Granex®,

Catalysis, S.L., Madrid, Spain, Aloe Vera is used as an auxiliary substance.

Numerous clinical studies of Granex®, Catalysis, S.L., Madrid, Spain, performed at

departments of dermatovenerology and gynaecology have proven its excellent properties,

such as the ability to heal viral as well as bacterial infections. Granex®, Catalysis, S.L.,

Madrid, Spain, was without any problems administered also to pregnant women. Excellent

effects following the application of the preparation in the initial stage of infections have been

described.

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Preliminary studies performed in 2004-2005 verified the expected very good effect in

a group of patients with acne vulgaris of mild and moderate severity (assessed according to

Cook’s acne severity grading scale 1-4) – 77,77%

Granex®, Catalysis, S.L., Madrid, Spain – other properties:

∗ neutral fragrance

∗ no risk of stains in case the preparation gets into contact with clothing

the preparation can be applied without any problems during pregnancy and lactation

Monitoring Granex®, Catalysis, S.L., Madrid, Spain in the study carried out

ought to prove the following effects:

∗ significant reduction in the number of comedones and inflammatory lesions

∗ decrease in sebum production by more than 20%

∗ permanent reduction in the number of comedones

∗ in comparison with oral antibiotics of tetracycline series, Granex®, Catalysis, S.L., Madrid,

Spain, is at an advantage, as it eliminates the risk of systemic adverse effects (such as

diarrhoea, vaginal Candida infections, photosensitivity)

∗ the undesired effects are insignificant and of transient nature

∗ in very few cases, slight skin dryness and transient skin erythema were reported as adverse

effects following the initial application

Furthermore, the already declared properties of Granex®, Catalysis, S.L.,

Madrid, Spain, ought to be proven, such as its very good tolerability, as well as the fact that

glycyrrhizinic acid and Aloe Vera significantly reduce skin irritation.

Annexed documents:

• Basic Working Protocol

• Inclusion and Exclusion Criteria

• Working and Evaluation Sheet

• Total number of patients

• Patient Consent Form

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In case you have any questions or concerns, please feel free to contact the Main Coordinator

of this study:

Hana Zelenková, M.D., Ph.,

Main Study Coordinator

In Svidník, as of 30.12.2005

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Annexes 1 -5

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Annex 1

Working Protocol regarding a patient included into the study titled: International, prospective, randomized, controlled multicentre study to prove the

efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Insurance company number:

Name of the patient:

Date of birth: Birth number: Sex

Address:

Occupation:

Diagnosis (acc. to Cook’s scale), notes:

Accessory diagnoses:

Other serious circumstances:

Date of study commencement:

Date of study termination:

Laboratory screening (significant pathological values):

Photodocumentation (number of pictures taken, date) –at inclusion into the study after

2, 4 and 8 weeks:

Therapy commencement

After 2 weeks

After 4 weeks

After 6 weeks

After 8 weeks

Total number

Granex: application: * affected areas shall be treated with Granex ® lotion and spray ∗Granex ® is applied 3 times a day during the first 10 days, after that 2 times a day on the whole face or other affected areas: Granex ® lotion is used to cleanse those areas followed by the application of Granex ® spray * the preparation is used until significant improvement of the condition of inflammatory lesions and reduction in comedones development takes place

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• application duration of minimum 4 weeks (max. 6 weeks, must be marked) • evaluation of facial skin lesions (at the inclusion into the series of patients and

after 2, 4 and 8 weeks • follow-up during 4 weeks after the termination of Granex ® application in order

to prove a continuous improvement of the finding of acne vulgaris Status localis: the monitoring of morphs and the following evaluation of facial manifestations as well as the overall severity of the manifestations according to the following system: number of non inflammatory lesions: on the right / on the left (open comedones, closed comedones), number of inflammatory lesions: on the right / on the left (papules)

Monitored morphs Status localis at therapy commencement







papules

(on the right/on the left)

pustules


nodules


Note: Neither pustules nor nodules ought to be present in patients included into the

study of Granex preparation

Status localis after therapy termination and grading according to Cook’s scale:



papules (on the right/on the left)

pustules (on the right/on the left)

nodules (on the right/on the left)

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Therapy duration in days:

Therapy interruption or discontinuation (including justification):

Therapy termination:

Evaluation of the therapeutic effect made by the therapist (1-5)*:

Self-evaluation made by the patient (1-5)*:

Adverse effects:

Other notes

Signature and stamp of the therapist

• Scale: 1– healing, 2 – significant improvement, 3 – improvement, 4 – no

improvement, 5 – aggravation

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Annex 2 International, prospective, randomized, controlled multicentre study to

prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity

grading scale 1-4)

Catalysis, S.L. Madrid, Spain

Inclusion Criteria • Disease: Acne vulgaris acc. to Cook’s scale graded 1 – 4 yes � no � • Disease duration of minimum 3 months yes � no � • Male, female, Caucasian yes � no � • Resistance to previously employed therapy yes � no � • Inpatient or outpatient yes � no � • Age: ≥ 16 years yes � no � • Voluntary participation in the study yes � no � • Consent declaration confirmation made in writing yes � no � • One-time participation in this study yes � no �

Exclusion Criteria

Specific Exclusion Criteria • Patients with untreated Diabetes mellitus yes � no � • In female patients, hormonal therapy employed within the previous 3 months yes � no � • Known allergies to the tested preparation yes � no� • Disease focus infection manifestations

(superinfection requiring therapy) yes � no� • Immunosuppressive therapy yes � no� • Cancer yes � no� • Malignancy in the observed area yes � no� • Employment of other drug and /or preparation in therapy yes � no� • Systemic therapy with antibiotics, retinoids yes � no� • Acne vulgaris acc to. Cook’s scale graded 5-8 yes � no� •

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General Exclusion Criteria:

• Drug and alcohol abuse yes � no � • Overuse of painkillers yes � no � • Pregnancy or lactation in female patients yes � no � • Participation in a clinical trial within the past 30 days yes � no � • Simultaneous participation in any other clinical study yes � no � • Other reasons excluding the patient from the study yes � no � • Restricted ability of the patient to follow therapy instructions yes � no � • Other physical or mental disorders disturbing the trial plan yes � no � • Possible consent withdrawal, presumed patient unreliability yes � no � •

Localisation: (insert yes, no)__________________________________ Face Chest Shoulders Back Other: Manifestation duration: days weeks months

Notes:

Date/stamp/signature

Ann

ex 3

Cat

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is S

.L.,

Mad

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and

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2. c

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C

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List

of P

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S.L

., M

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in

Page

1 /

1

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: In

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s (m

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)

Fu

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and

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)

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Annex 5 Trial Performance Centre: Therapist: I ......................................................................... (full name) have been fully and comprehensibly instructed in and advised on the nature, purpose and potential contribution of the study titled:

International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with

acne vulgaris by: and I have been given enough time to decide upon my participation in this clinical trial. I have been influenced or by any means forced neither by my therapist nor any other clinic staff member. I have received patient information in writing and I have read it carefully and understood it thoroughly. I have been instructed in the principles of health insurance as well as in my obligations resulting thereof. I agree to my participation in this study and understand that I am free to withdraw my consent at any time without having to give a reason. I give my permission for other experts to carry out examinations with the consent of my therapist exclusively, except in case of evident emergency, and understand that I am not allowed to participate in any other clinical trial. I understand that any adverse effects or health damage that may result from this clinical trial must be reported to my therapist without unreasonable delay. 1. Confirmation of Consent: I hereby give and confirm my consent for the information

gained in the course of this study, including information about the disease, to be recorded on the forms as well as digital media and submitted without my name attached:

a) to the party ordering this study Catalysis, S.L., Madrid, Spain, for further evaluation Apart from that, I give my permission for the pictures of the affected skin to be taken.

Moreover, I give my consent for the publication of anonymous photo documentation to be performed. I have received a copy of Patient Consent Form to keep. The other copy remains with my therapist responsible for the trial. I have received a copy of the patient information sheet as well as the insurance conditions forms to keep. place, date Patient signature place, date Trial performing Therapist signature

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Annex II – Tables and Graphs

TAB No 1Basic data on patients included into the clinical trial:Working Protocol regarding a patient included into the study:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Center men ø age women ø age B C D1 2 22 8 20.15 31,5 0 02 0 0 10 20,2 32,5 0 03 2 20,12 8 22,8 50,8 0 04 2 19,1 8 22,1 39,2 0 05 4 17,1 6 16,5 31,2 0 06 6 16 4 16,2 30 0 07 4 18,1 6 17,2 28 0 08 5 17,6 5 16,9 30 0 09 3 25,6 7 23,5 28 1 010 2 26,8 8 28,2 28 0 011 7 17 3 18 32 0 0

Total 37 73Percentage 33,64% 66,36%Average 18,13 20,16 32,84

B – application duration in days – mean durationC – adverse effects D – relapses within 30 day, 0 - none

Graph No 1

Basic data on patients included into the clinical trial - number men and women:Working Protocol regarding a patient included into the study:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Graph No 2Basic data on patients included into the clinical trial - average age men and women:Working Protocol regarding a patient included into the study:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

2

8

0

10

2

8

2

8

4

6

6

4

4

6

5

5

3

7

2

8

7 3

0123456789

10

1 2 3 4 5 6 7 8 9 10 11

centers

Preparation containing glycyrrhizinie acid in patients with acne vulgaris - number men and women

menwomen

18,13

20,16

17

17,5

18

18,5

19

19,5

20

20,5

men women

Average age of men and women - preparation containing glycyrrhizinie acid in patients with acne vulgaris

TAB No 2Efficacy and tolerability of the preparation in patients included into the clinical trial:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4))

Center E1 3x1 6x2 1x3 8x1 2x2 5x1 4x2 1x3 9x1 1x2 02 4x1 5x2 1x3 7x1 3x2 6x1 3x2 1x3 8x1 2x2 03 10x1 10x1 10x1 10x1 04 7x1 2x2 1x3 9x1 1x2 7x1 2x2 1x3 9x1 1x2 05 3x1 6x2 1x3 8x1 2x2 7x1 2x2 1x3 8x1 2x2 06 6x1 4x2 10x1 6x1 4x2 10x1 07 7x1 3x2 8x1 2x2 8x1 2x2 9x1 1x2 08 6x1 3x2 1x3 8x1 2x2 6x1 3x2 1x3 8x1 2x2 09 3x1 6x2 1x3 7x1 2x3 3x1 6x2 1x3 7x1 2x2 1

10 3x1 6x2 1x3 7x1 3x2 4x1 5x2 1x3 7x1 3x2 011 5x1 2x2 3x3 10x1 5x1 2x2 3x3 10x1 0

Total 57 43 10 92 15 2 67 33 10 95 14 1Percentage 51,82% 39,09% 9,09% 84,40% 13,76% 1,83% 60,91% 30,00% 9,09% 87,16% 12,84% 0,91%

patients/assessed according to the scale

TE/TT – assessment made by the therapist – TE therapist efficacy /TT therapist tolerabilityPE/PZ - assessment made by the patient PE patient efficacy/PT patient tolerabilityE - discontinuation

efficacy:1 - healing2 - significant improvement 2 - good3 - improvement 3 – without effect4 - no improvement5 - aggravation

tolerability:1- excellent

4 - irritation

TE PETT PT

Graph No 3Efficacy and tolerability of the preparation in patients included into the clinical trial:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4))

Graph No 4Efficacy and tolerability of the preparation in patients included into the clinical trial:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerabilityof a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4))

Graph No 5

65

0

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43 3

6 6

23 4

107

36 7 6

3 35

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10

1.cen

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Assessment of the efficacy of the preparation made by the therapist

healingsignificant improvementimprovementno improvementaggravation

8 710 9 8

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Assessment of the tolerability of the preparation made by the therapist

excellentgoodwithout effectirritation

Efficacy and tolerability of the preparation in patients included into the clinical trial:International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4))


Graph No 7Efficacy and tolerability of the preparation in patients included into the clinical trial:

0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 01 1

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Assessment of the efficacy of the preparation made bythe patient

healingsignificant improvementimprovementno improvementaggravation

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Assessment of the tolerability of the preparation made by the patient

excellentgoodwithout effectirritation

International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerabilityof a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4))

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TE TT TE TT TE TT TE TT TE TT TE TT TE TT TE TT TE TT TE TT TE TT

1.center 2.center 3.center 4.center 5.center 6.center 7.center 8.center 9.center 10.center 11.center

Assessment of the efficacy and tolerability of the preparation made by the therapist

TE - therapist efficacy TT - therapist tolerability

healing / excellent significant improvement / goodimprovement / without effect no improvement / irritationaggravation



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PE PT PE PT PE PT PE PT PE PT PE PT PE PT PE PT PE PT PE PT PE PT

1.center 2.center 3.center 4.center 5.center 6.center 7.center 8.center 9.center 10.center 11.center

Assessment of the efficacy and tolerability of the preparation made by the patient

PE - patient efficacy PT - patient tolerability

healing / excellent significant improvement / goodimprovement / without effect no improvement / irritationaggravation



020406080

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efficacy tolerability

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healing significantimprovement

improvement noimprovement

aggravation


efficacytolerability

A t f th ffi d t l bilit f th ti



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healing improvement aggravation

efficacy

tolerability

Assessment of the efficacy and tolerability of the preparation made by the patient


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aggravation

Assessment of the efficacy and tolerability of the preparationmade by the patient


Comparison of efficacy of the preparation containing



Comparison of efficacy of the preparation containing glycyrrhizinic acid made by both the therapist and the patient

10=9%

33=30%

10=9%

57=52%43=39%

67=61%

healing

significantimprovementimprovement

no improvement

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aggravation

Comparison of efficacy of the preparation containing glycyrrhizinic acid made by both the therapist and the patient

therapistpatient

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excellent good without effect irritation

Comparison of tolerability of the preparation containing glycyrrhizinic acid made by both the therapist and the patient

therapistpatient

TAB No 3Persistence of effect after 4 weeks following the termination of application: International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Centrum1 8x1 2x22 9x1 1x23 9x1 1x24 8x1 2x25 7x1 3x26 8x1 2x27 8x1 2x28 7x1 3x29 8x1 1x2

10 7x1 3x211 8x1 2x2

Total 87 22Percentage 79,82% 20,18%

F - Persistence of effect after 4 weeks following the termination of application 1 - excellent2 - slight aggravation3 - significant aggravation

Graph No 16

F

Persistence of effect after 4 weeks following the termination of application: International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Graph No 17Persistence of effect after 4 weeks following the termination of application: International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

8 9 9 8 7 8 8 7 8 7 8

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significant aggravation

slight aggravation

excellent

Persistence of effect after 4 weeks following the termination of application (8th monitoring week)

significant aggravation slight aggravation excellent

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excellent slight aggravation significant aggravation

Persistence of effect after 4 weeks following the termination of application

TAB No 4 Assessment made according to Cook’s acne severity grading scale 1-4, by comparing the condition prior to therapy commencement and upon its termination . International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Center I II III 1 8x4 2x3 8x1 1x2 1x3 2 6x4 3x3 1x2 8x1 1x2 1x3 3 8x4 1x3 1x2 8x1 2x2 4 7x4 1x3 2x2 8x1 1x2 1x3 5 8x4 1x3 1x2 7x1 2x2 1x3 6 7x4 2x3 1x2 6x1 4x2 7 7x4 2x3 1x2 6x1 3x2 1x3 8 7x4 1x3 2x2 8x1 1x2 1x3 9 7x4 3x3 7x1 2x2 1

10 8x4 2x3 8x1 2x2 11 9x4 1x3 5x1 5x2

Total 82 19 9 79 24 6 Percentage 74,55% 17,27% 8,18% 71,82% 21,82% 5,45% I- Grading acc. to Cook prior to inclusion number of patients/grade Cook II- Grading acc. to Cook upon therapy termination III- exclusion

Graph No 18 Assessment made according to Cook’s acne severity grading scale 1-4, by comparing the condition prior to therapy commencement and upon its termination . International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

86

8 7 8 7 7 7 7 8 9

2 31 1 1 2 2 1

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Graph No 19 Assessment made according to Cook’s acne severity grading scale 1-4, by comparing the condition prior to therapy commencement and upon its termination . International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris (Cook’s acne severity grading scale 1-4)

Graph No 20 Assessment made according to Cook’s acne severity grading scale 1-4, by comparing the condition prior to therapy commencement and upon its termination . International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris

Graph No 21Assessment made according to Cook’s acne severity grading scale 1-4, by comparing the condition prior to therapy commencement and upon its termination . International, prospective, randomized, controlled multicentre study to prove the efficacy and tolerability of a preparation containing glycyrrhizinic acid in patients with acne vulgaris

56

Annex III - Photodocumetation

Clinic No 1 – before an after therapy












69

Annex IV - Photodocumetation – summary

Clinic No 1 - photo-documentation chosen subject











Documents

International study in patients with acne · Bibliography 20 Annex I 22 - 29 Annex 1 – 5 30 - 38 Annex II – Tables + Graphs 39 - 55 Annex III - Photodocumetation 56 - 68 ... acne