Effectiveness of Blue-Cap/Viusid in the treatment of Atopic ... - … · A descriptive –...

ISCM- H. Manuel Fajardo Faculty of Medicine

Dermatology Service

Effectiveness of Blue-Cap/Viusid in the treatment of Atopic Dermatitis

Researchers: Dr. Alfredo Abreu Daniel* Dr. Ramón Daniel Simón**

Dr. Lisbet Rodríguez de Armas***

* Head Professor and Consultant. Level II Dermatology Specialist

** Dr. in Medical Sciences. Head Professor. Level II Dermatology Specialist *** Level I specialist in Comprehensive General Medicine

Year Dermatology Resident

Research Study to Opt to the Level 1 Dermatology Specialist Degree

2008

Index Abstract ......................................................................... ¡Error! Marcador no definido.3

Introduction .................................................................. ¡Error! Marcador no definido.4

Objectives ....................................................................................................................... 14

Method ............................................................................................................................ 15

Results and discussion ................................................ ¡Error! Marcador no definido.22

Conclusions .................................................................................................................... 32

Recommendations .......................................................................................................... 32

Bibliography ............................................................... ¡Error! Marcador no definido.33

Annexes .......................................................................................................................... 37

Abstract

A descriptive – prospective Stage III study was conducted on children with Atopic Dermatitis

who were being treated at the specialized consultation of the Hospital Pediátrico

Universitario Pedro Borrás Astorga Paediatric Hospital (City of Havana), for the purpose of

describing the behaviour of this diseases according to: gender, skin colour, age groups, injury

location, the disease’s previous time of development, personal and family pathological

history, and aggravating factors. A second purpose of the study was to assess the therapeutic

effects of Blue-Cap (topical) and Viusid (oral) and identify any side effects. The research

included thirty patients from Havana, with clinical diagnosis by excellence. Clinical response

was assessed in accordance with the Dermatitis Assay Score Index (DASI). A majority of

patients were females, mixed-race skin coloured aged 7-10. Occurrence was more common on

the flexural area, and the time of evolution of injuries observed was under one month. Allergic

Rhinitis was the most often reported personal pathological background, while Bronchial

Asthma was the most common family pathological background. The most significant

aggravating factors were environmental and diet-related. Blue-Cap and Viusid have beneficial

effects and the use of the drugs did not trigger any significant side effects.

Keywords: Atopic Dermatitis. Blue-Cap. Viusid.

Introduction

Atopic Dermatitis (AD), Eczemas: atopic, infant or constitutional, Neurodermatitis, Besnier’s

Prurigo or Flexural Dermatitis (1, 2) was described several centuries ago, reported by Brocq &

Jaquet in 1891 as Disseminated Neurodermatitis, and one year later as Diathesic Prurigo by

Besnier. In 1923, Coca & Cooke suggested the term atopy (Greek for “out of place”) and, in

1933, Hill & Sulzberger gave it the name it has been known by to date.

AD is a chronic and relapsing inflammatory disease of the skin, of multi-factor etiology,

frequently associated with a family or personal background of atopy, characterized by typical

morphological and topographic alterations such as dry skin and intense pruritus. (2)

AD is a cosmopolitan entity that has become two to three times more prevalent in the last

three decades, affecting 10%-20% of the infant population (3) and 1%-3% of adults (4.5).

Multiple theories have attempted to explain the causes of dermatosis, the most relevant of

which are:

Genetic Theory: A background of personal and / or family atopy for 50%-70% of cases.

Autosomal dominant inheritance with variable expressivity is proposed. If a parent is

atopic, the probability of atopy in the child is 60%; if both parents are atopic, the

probability increases to 80%. Chromosome 11q13 defect. Genetic alteration of membrane

proteins in the atopic monocyte, which increase the production of phosphodiesterases and

prostaglandin E2. Anomalous expression of the IL-4 gene. Chromosome 5q 31-33, which

encodes the cytokine gene family IL-3, 4, 5, 13 and GM-CSF expressed by TH-2

lymphocytes. (2,6)

Immunological Theory: increase of the humoral immunity with increased B-cell activity

and IgE production, which foster the secretion of pro-inflammatories and depression of

cell immunity with defect in the maturation of T-cells, and increase of cooperating T-cells

(TH-1 that mediate late hypersensitivity reactions, recruit monocytes and macrophages in

intra-cell infections, and induce production of cytolytics in LT and TH-2, which in turn

produce large quantities of IL-4, 5, 13, which are powerful inducers of eosinophiles and

IgE); and decreasing T-suppressor (TS) lymphocytes; large quantities of monocytes,

eosinophiles, macrophages, mastocytes and Langerhans’ cells; increase of IL-2; marked

reduction of phagocytosis and chemotaxis of atopic monocytes and neutrophils; increase

of eosinophiles in both blood and skin. (2,7,8,9)

Allergic Theory: A background of personal and / or family atopy for 70% of cases.

Increase of IgE in 80% of cases. The AD can be exacerbated by environmental allergens

such as: pollen, house dust, feathers, animal dandruff, herbs, wool, satin, silk, cosmetic

soaps, domestic detergents, antiseptic products (2, 10, 11) or food products including:

eggs, peanuts, cow’s milk, wheat and soy in children. (3, 12, 13, 14, 15, 16). The role of

the IgE y TH-2 is crucial in the pathogenesis of DA. (17)

Infectious theory: S. aureus colonies increase in 90% of patients, with the production of

exotoxins (teichoic acid, peptidoglycans and protein A) which can release histamine from

basophiles, which worsen and perpetuate the symptoms, and superantigens that foster the

production of IL-1, 2 and TNF; IgE has been detected against S. aureus in 57% of cases,

which aggravates symptoms, as well as IgE against P. ovale (15%-65%) coexisting with

seborrheic dermatitis. (2,18,19,20,21)

Neurovegetative theory: abnormal reaction of the Autonomous Nervous System with

sustained vasoconstriction and slow response to intradermal histamine. Altered reaction to

hot and cold (extreme temperatures or sharp temperature changes) (2,11,22,23,24)

Psychological or Emotional Theory: one of the oldest and most argued theories, associated

with “atopic” personality (anxiety, irritability, hostility, emotional lability) and

emotionally-charged events. (1,2,3,11,22,25,26)

Symptoms are usually characteristic, featuring typical and atypical manifestations including

extremely paroxystic pruritus as cardinal symptom that, along with scratching, leads to skin

changes.

Typical manifestations involve three development stages according to patient age and location

of injuries (the AD may follow this process with or without latency periods, or even start or

heal in any stage), which are the following:

Nursing infant stage: two-month – two-year old children; erythemic – exudative -

scabbing injuries on: scalp, cheeks, chin (excepting centrofacial region), may spread to

hands, trunk anterior side, limb extensor surfaces, or spread to wider regions, leading to

Hill’s or atopic erythroderma; it occasionally triggers worsening of the newborn’s milium,

diaper rash or lacteal cradle cap.

Child stage: two - ten year old children, rare after age seven; drier l lichenified, excoriated

injuries on: elbow and knee folds, ankles, wrists or retroauricular folds, periorbital and

peribuccal areas.

Adult stage: adolescence to adulthood, rare from age forty; lichenified lesions on: neck,

neck sides, wrists, foot dorsum, folds: antecubital, popliteal, face and hands. (1,3,11,21,25)

Atypical occurrences include the following:

- Pityriasis Alba

- Eczema Areola

- Immediate type-I skin reaction tests

- Increased serum IgE

- Occurrence in early childhood

- Symptoms and signs influenced by environmental and emotional factors

- White dermographism (3,4,11,21)

- Dishydrosis

- Juvenile Plantar Dermatitis (1,21)

- Atopic cheilitis (1,3,11,21)

- Atopic xerosis

- Follicular keratosis

- Dennie-Morgan infraorbital fold

- Accentuation of folds: palmar, plantar and neck

- Ichthyosis Vulgaris

- Tendency to skin infections (staphilococci, herpes simplex, molluscum contagiosum,

warts)

- Anterior subcapsular cataracts

- Facial paleness / facial erythema (2,3,4,11,21)

- Repeated folliculitis

- Hypersensitivity to insect bites

- External acoustic ematus eczema (21)

- Intolerance to wool and lipid solvents

- Food intolerance

- Pruritus when sweating (3,11,21)

- Tendency to non-specific hand and foot Dermatitis

- Orbital darkening

- Keratoconus (2,3,4,11)

- Perifollicular accentuation (3,11)

- Bluish sclerae

- Skin hypothermia

- Alteration of immunity mediated by cells

- Erythroderma (11)

- Recurrent conjunctivitis (2,3,11,21)

The diagnosis of Atopic Eczema requires at least three major criteria (pruritus, damage with

morphology and typical distributions “flexural o linear lichenification in adults”- “facial or

extensor area commitment in infants”, chronic or relapsing dermatitis, and either personal or

family history of atopy “asthma, rhinitis, DA”) along with three minor criteria or atypical

occurrences. (2, 3, 4, 11, 21, 27)

This dermatosis can involve multiple complications, such as:

1. Bacterial Sepsis: Occurs frequently during acute or sub-acute stages, and it is known as

Impetiginized Eczema.

2. Molluscum Contagiosum and Warts: the atopy favours the occurrence of viruses causing

said entities.

3. Kaposi varicelliform eruption: secondary infection triggered by either smallpox virus or

herpes simplex, which leads to severe disseminated erythematous - vesicular eruption

affecting the Central Nervous System.

4. Wiscott - Aldrich syndrome: Rare disorder in which the eczema is present along with

haemorrhages from excoriations, passed on as a recessive trait connected to chromosome

X, which increases the susceptibility of children to leukaemias, lymphomas and

autoimmune phenomena. (8)

A successful treatment of AD requires a systematic and multi-factorial approach involving the

following: identification and abolition of aggravating factors, skin hydration and use of drugs,

personalized according to each individual’s skin reaction patterns and focused on three key

mainstays of action, which are:

1. General Measures

2. Topical Treatment

3. Systemic Treatment (4)

1. General Measures:

• Clear explanation to patient and relatives of: the chronicity of AD, triggering factors, the

impossibility of changing skin type, and the need to follow the therapy strictly. (11)

• Avoid contact with: soaps, cleaners, alcohol, chemicals; smoke, dust, animal fur, mould,

pollen; heat (4); wool, plastic, rubber; environmental dryness, excessive sunlight; live

virus vaccination during systemic steroid treatment (chicken pox, poliomyelitis, parotiditis

parotitis, German measles, measles); hot water.

• Ensure that children do not ingest: cow’s milk, soy, peanuts, fish, citruses, tomatoes,

cocoa, coffee, alcohol, strawberries, seafood.

• Simultaneous and correct control of other atopies.

• Apply emollients immediately after a brief bath with lukewarm water showers and body

wash with acid ph. (28,29,30)

• Avoid sharp temperature changes and any situations that could cause excessive sweating,

such as: emotional stress and sports. (1,2,11,21,22,25)

• Promote hypoallergenic diets during pregnancy with risk of having atopic children, and

Exclusive Breastfeeding during the first four months of life and up to six or nine months.

(2,11,22)

• Use gloves and cut nails appropriately. (21,25)

2. Topical Treatment:

• Skin hydration with lukewarm water baths for at least twenty minutes, or wet dressings on

hard-to-control AD, followed by the application of an occlusive emollient (emulsifying

ointments, lanolin, liquid paraffin, urea, Vaseline, glycerine, squalane, lactic acid,

ammonium lactate, coal tar 1%-5%, or liquor carbonis detergens 5%-10% on hydrophilic

ointments). (3,4,8,31)

• Topical glucochorticoids: they are the keystone of AD treatments. Applied on: face,

genitals and intertriginous areas, low strength products recommended; intermediate

strength on trunk and limbs; an ultra-high strength for short periods of time on lichenified

non-absorbent areas; apply gel on scalp or beard. (4) Apply dressings if excoriation

predominates. Combined them with: neomycin, tetracycline, fusidic acid or quinolone on

light bacterial sepsis. Bear in mind local and systemic side effects.

• Cryotherapy: for warts and molluscum contagiosum.

• Aciclovir (cream 5%): Applied five times daily over Kaposi varicelliform. (8)

• Topical antiseptics: solutions including: Burow, Alibour (3), copper sulphate, sodium

borate and potassium permanganate for acute AD. (31)

• Tacrolimus (FK-506 or Protopic ointment): Topical immunosuppressant, harmless and

effective, which inhibits calcineurin and halts the activation of T-cells, Langerhans’ cells,

mastocytes and keratinocytes. 0.03% used on moderate AD, short- or long-term on

children aged 2-15, and 0.03% / 0.1% on AD for adults.

(1,3,4,11,22,28,31,32,33,34,35,36,37,38)

• Pimecrolimus (SDZ ASM 981 or Elidel cream): Topical immunomodulator that locks

macrophilin-12 and inhibits calcineurin, cytokines and intermediates from mastocytes and

basophiles. Useful on AD. (3,4,11,22,28,31,32,39)

• Topical mupirocin: Useful for treatment of impetiginised lesions.

• Topical antimycotics: on dermatophytosis or IgE antibodies against P. ovale. (2,4)

• Coal tar products: antipruriginous and light anti-inflammatory effects, enables the

reduction of the strength of glucocorticoids in AD maintenance therapy. Effective

shampoos for scalp dermatitis. Dressings soaked in tar are very useful for Besnier’s

prurigo. Side effects: folliculitis, irritation, photosensitivity and perhaps carcinogenesis.

(4,8)

• Phototherapy: Broadband ultraviolet B and A radiation, narrowband ultraviolet B

radiation, UVA-1, UVAB are useful for AD therapy; PUVA for cases of severe

disseminated AD. Short-term side effects include: erythema, pain, pruritus and skin

pigmentation. Long-term side effects: premature ageing and development of malign skin

processes. (3,4,28,31,32)

• Phosphodiesterase inhibitors: topical application is effective on AD. (4,31)

• Extracorporeal photopheresis: effective on severe refractory AD when combined with

topical steroids. (4)

• Gentaderm B (cream): useful for AD. (40)

• Labosalic (ointment): includes betamethasone dipropionate and salicylic acid, effective for

sub-acute and chronic AD. (41)

• Skin-Cap (shampoo, spray, cream, body wash): Effective on AD according to evidence

provided by clinical research conducted in several countries. (42)

3. Systemic Treatment:

• Systemic antihistamines: non-sedative products can be useful for AD with nettle rash;

sedatives (hydroxyzine, diphenhydramine) are preferable at night. Doxepin chlorhydrate

(tricyclic antidepressant, H1-H2 receptor blocker) can be administered orally to adults on

10 mg – 75 mg doses at night, or up to 75 mg every 12 hours. (4,43)

• Systemic glucocorticoids: for acute AD exacerbations for a short time. (4,28)

• Recombinant Gamma and Alpha Interferons: clinically improve AD. (1,4,31,32,44)

• Cyclosporine: Powerful immunosuppressant that inhibits cytokine transcription. Effective

on children and adults with severe refractory AD in conventional therapy, for short periods

of time, involving 5mg/kg doses or 150-300mg/day microemulsion of said substance on

adults. Side effects: nephrotoxicity, hypertension and rebound effect on discontinuance.

(1,2,4)

• Thalidomide: Effective on AD with 25-100mg doses. (2)

• Immunotherapy with allergens: for AD induced by aeroallergens.

• Mycophenolate Mofetil (MFM): Antimetabolite used on adults with refractory AD in

conventional therapy, (2g/day oral) for a short period of time. (4)

• Methotrexate: Antimetabolite that inhibits the synthesis of cell chemotaxis and cytokines.

Used for refractory AD to other modalities, in 12.5-25 mg Im/week or 2.5 mg/day 4 days /

week oral doses. It causes myelosupression.

• Azathioprine: Analogous to purines, anti-inflammatory - antiproliferative used for severe

AD, 100-200 mg/day oral. (4, 28)

• Zafirlukast: Effective for severe AD with con 20mg oral doses every 12 hours. (45)

• Oral antibiotics: useful for major superinfections. Erythromycin, azythromycin,

claritromycin, first generation cephalosporins for S. aureus infections; dicloxacillin,

oxacillin or cloxacillin for macrolide-resistant S. aureus infections. (1,2,4,28).

• Aciclovir: oral dose of 400mg every 8 hours or 200mg every 6 hours for ten days is

effective in the treatment of skin herpes simplex on adults. Intravenous application for

disseminated eczema herpeticum. Adapt the dose for children according to body weight.

• Systemic antimicotic: for dermatophytosis or IgE antibodies against P. ovale. (4)

Other therapeutic methods:

• Oils: fish oil (a source of essential Omega-3 fat oils) and oil extracted from Oenothera

biennis seeds (a source of essential Omega-6 fat oils) were not effective in the treatment of

AD. (4)

• Chinese herbs: currently under research. Risk of cardiac and hepatic damage. (2,4,46)

• Hospitalization: for cases of erythrodermia or outpatient treatment-resistant severe

disseminated AD. (4,8,28)

• Symbiotics and Probiotics: improve AD on children aged 2 and over. (47)

In Cuba, the therapy for this dermatosis is based on the following three key points:

1. General measures:

• In-depth explanation to patient describing the characteristics of the entity (personal and

family history of atopy is required beforehand).

• Explaining that it is essential to detect and stay away from all harmful agents (soap,

cleaner, rubber, wool, plastic, polyester, oilskin, nylon, pesticides, fertilizers, petrol,

kerosene, paint products, cement, dyes, cosmetic products, ultraviolet light, traumas,

rubbing).

• Avoidance of self-medication.

• Undergo medical dermatology tests in the event of occupational dermatitis.

2. Topical treatment:

Acute Stage: • Generalized lesions: Starch, oats and camomile baths.

• With added bacterial infection: zinc and copper sulphate baths.

• Localized lesions: camomile, saline solution and aluminium acetate fomentations.

• With added bacterial infection: potassium permanganate and acriflavin fomentations.

Subacute Stage: • As above plus the following: liniments, emulsions, lotions and corticosteroid creams on

the driest areas. (48)

Chronic Stage: • Corticosteroid creams: Budesonide. (49)

• Ointments, keratoplasties and keratolytics: tar and salicylic acid on lichenified areas,

occasionally.

3. Systemic Treatment:

• Sedatives and Antihistamines.

• Systemic steroids: avoid them. Only use them for superacute cases in which the aggressive

substance can be completely removed.

• Systemic antibiotics: Tetracycline and doxycycline on infected AD. (48)

• Transfer factor (Hebertrans): useful for AD, IM or SC. (50)

Blue Cap is a new range of dermatological products featuring five different forms: spray,

shampoo, gel and cream for topical application and capsules for internal use. Its positive

effects are based on the specific properties of the new formulation for zinc pyrithione, which

provides a high anti-bacterial action against staphylococci and streptococci, and anti-fungal

action against pityrosporum: ovale and orbiculare. It also acts against micro-organisms on

both the surface and inside the corneal layer, thanks to its antiproliferative and cytostatic

effect that stabilizes enzymes and notably improves cell membranes. The secret behind its

high level of effectiveness is based on the process of molecular activation undergone by its

natural ingredients. It is harmless if administered as recommended herein. Advantages:

effective and fast-performing, includes absolutely no corticosteroid or cytostatic substances,

and can deeply hydrate and penetrate the skin. The total absence of side effects enables the use

of this product on all types of patients, including children, during the required time of

treatment.

Clinical research conducted in several countries to date have confirmed the excellent

performance of this product against Atopic Dermatitis, concluding that either good or

excellent results are achieved from the sixth day of treatment, specifically with the spray and

shampoo. Also, it offers excellent absorption, with no side effects and better results as

compared with other previously used products. (51)

Viusid is a nutritional supplement available in two different forms with similar composition:

mixture and sachets. Components include: amino acids, vitamins and trace elements found

naturally in the human organism, which operate as biocatalysts and immunostimulants. It is a

powerful antioxidant and interferon inducer that does neither cause toxicity nor side effects

after application. (52). In addition, it features anti-viral properties. (53)

The high level of occurrence and prevalence of Atopic Dermatitis, along with the introduction

of these new highly effective and fast-performing, has led us to conduct this clinical research

study in our country.

Objectives General:

To assess the therapeutic effectiveness of Blue-Cap/Viusid in the treatment of Atopic

Dermatitis.

Specific:

1. To assess the therapeutic effect of both Blue-Cap and Viusid in the treatment of Atopic

Dermatitis.

2. Characterization of the universe of patients under study according to: gender, skin

colour, age groups, injury location, previous lesion development time, pathological

personal and family history, and this entity’s aggravating factors.

3. Identification of all side effects detected.

Method This research was conducted in association with Laboratorios Catalysis, Madrid, Spain.

Clinical Trial Characteristics

A descriptive, prospective stage III clinical trial was conducted. The trial was started

following approval of the corresponding Clinical Research Study by the Ethics Committee.

Formulation

Blue Cap is a new range of dermatological products manufactured by Laboratorios Catalysis

(Madrid, Spain) featuring five different forms: spray, shampoo, gel and cream for topical

application and capsules for internal use. It contains zinc pyrithione, which provides a high

anti-bacterial action against staphylococci and streptococci, and anti-fungal action against

pityrosporum: ovale and orbiculare. It also stabilizes enzymes and notably improves cell

membranes. The product was presented in gel and cream forms.

Blue-Cap composition (cream) :

- Zinc pyrithione 0.2%

- Excipient, q.s.

Blue-Cap presentation (cream):

- 50 g tube

Blue-Cap composition (gel):

- Zinc pyrithione 0,5%

- Excipient, q.s.

Blue-Cap presentation (gel):

- 400 ml bottle

The other product included in the study was Viusid, a nutritional supplement available in two

different forms (mixture and sachets) with similar compositions. Its amino acids, vitamins and

trace elements are found naturally in the human organism, operating as biocatalysts and

immunostimulants. An interferon inducer and powerful antioxidant with antiviral properties.

Presented in sachets.

Viusid is a nutritional supplement available in two different forms with similar composition:

mixture and sachets. Components include: amino acids, vitamins and trace elements found

naturally in the human organism, which operate as biocatalysts and immunostimulants. It is a

powerful antioxidant and interferon inducer that does neither cause toxicity nor side effects

after application. (52). In addition, it features anti-viral properties.

Viusid composition (sachets):

Ingredients: Daily dose: Malic Acid 0.666 g

Glucosamine 0.666 g

Arginine 0.666 g

Glycine 0.333 g

Glycyrrhizinic acid 0.033 g

Ascorbic acid 0.020 g

Zinc sulphate 0.005 g

Calcium panthotenate 0.002 g

Piridoxal 0.600 mg

Folic acid 66.000 mcg

Cyanocobalamin 0.300 mcg

Sodium Methylparaben 0.003 g

Neohesperidin 0.005 g

Lemon 0.666 g

Peppermint 0.033 g

Honey 0.833 g

Guar Gum 0.068 g

Chemical - biological composition of Viusid:

Aspects Approximate values Net

- Weight per sachet 4 g ± 10% 4.2 g

- Aspect Yellowy powder Yellowy powder

- Humidity (%) 5% ± 10% 4.9%

- Ashes (%) 22% ± 2% 21.8%

- Carbohydrates (%) 19% ± 5% 18.9%

- Proteins (%) 53% ± 5% 53.2%

- Fats (%) 1.8% ± 10% 1.8%

- Total Kilojoules Kjul/100g 1284 Kjul/100g ± 5% 1280 Kjul

- Total Kilocalories Kcal/100g 302 Kcal/100g ± 5% 302 Kcal

Viusid presentation (sachets):

90-sachet boxes (4g each)

Patient universe

Prior informed consent signed by patients (Annexe 1), we selected 30 patients with Atopic

Dermatitis regardless of gender or skin colour, all with clinical symptoms of Atopic

Dermatitis and clinical histopathology for patients with unclear symptoms. All selected

patients who came to the Atopic Dermatitis specialist office of the Hospital Pediátrico

Universitario Pedro Borrás Astorga hospital met all inclusion criteria set for this study.

Inclusion criteria

• Age: 2-month-old to 10 year-old children.

• Informed consent signed by the patient and the General Practitioner.

• Atopic Dermatitis covering 2% - 35% of the affected body surface, in accordance with the

results obtained with the Lesion Location Form (Annexe 2).

• Patients who had not undergone any treatment within the previous two weeks.

Exclusion criteria

• Failing to meet any of the aforementioned inclusion criteria.

• Patients with dermatophy other than atopic.

• Acute infectious diseases, whether severe or convalescent.

• Atopic Dermatitis with superadded infection.

Groups and treatment

After signing and delivering the corresponding informed consent document, patients were

included in two groups of fifteen children each, selected by simple random sampling. Besides

orally administered Viusid (sachets, twice daily), one group also received treatment with

Blue-Cap (cream) applied twice daily, and the other Blue-Cap (gel) once daily for six weeks

for a total of thirty patients undergoing treatment.

Patients received verbal and written instructions on the application and administration of the

products, including the ingestion of the contents of a Viusid sachet every 12 hours after each

meal, diluted in milk, drinking water or fruit juice —at home and under the supervision of

their parents. The application of Blue-Cap (cream) first thing in the morning (half an hour

before dressing) and in the evening two hours before going to bed, and Blue-Cap (gel) during

the bath.

Assessment of lesions

We conducted initial and also fortnightly clinical assessment of each patient during the time of

application of the treatment for six weeks, as well as macroscopic distribution of lesions,

quantifying the areas affected, which were drawn by specialists on Case Report Forms (CRF),

recorded with specific frequency: upon inclusion and fortnightly until completion of the

treatment. General data corresponding to patients undergoing treatment, initial assessment and

all assessments carried out during the study were recorded on the respective CRFs. Also

recorded on the CRFs were the clinical response variables including the following: erythema,

excoriation, dryness, cracks, lichenification and affected area, as well as pruritus and side

effects if any (Annexe 2). Assessment was conducted by means of clinical inspection in each

consultation. The response to the treatment was calculated with the Dermatitis Assay Score

Index (DASI) for each patient, using the clinical response variables specified on the CRFs

(Annexe 3, Annexe 4).

Pruritus:

0. Absent

1. Occasional

2. Present, does not affect sleep pattern

3. Impertinent, increases during the night, may disrupt sleep pattern

4. Severe, distressing, keeps the patient awake during the night

Affected area:

0. Lesion-free area

1. 1%-10% of the area with lesions






Erythema, excoriation, dryness, cracks and lichenification:

0. Absent

1. Slight (requires careful inspection to detect signs)

2. Moderate (immediately visible signs)

3. Intense (prominent signs)

4. Exceptionally intense (very prominent signs)

The DASI was calculated as follows:

DASI = 0.1 x (erythema + excoriation + dryness + cracks + lichenification) x head and neck

area.

+ 0.2 x (erythema + excoriation + dryness + cracks + lichenification) x trunk area.

+ 0.4 x (erythema + excoriation + dryness + cracks + lichenification) x upper limbs’

area.

+ 0.3 x (erythema + excoriation + dryness + cracks + lichenification) x lower limbs’

area.

The total assessment time was six weeks for patients who received both forms of Blue-Cap

and Viusid sachets.

Semantic control

Dermatitis Assay Score Index (DASI): an international quantitative method applied to

therapeutic tests for clinical assessment of the response of patients with dermatitis. It is

obtained by combining in a mathematical formula the value given by the specialist physician

to the affected body area and the intensity of the erythema, excoriation, dryness, cracks and

lichenification found in said area.

Initial DASI: the DASI presented by the patient at the time of inclusion to this study, prior

undergoing the treatment, is considered.

Response to the treatment:

Clean or Virtually Clean: a patient whose DASI decreases by at least 90% in relation to the

initial DASI.

Responsive: a patient whose DASI decreases by 89.9% - 51%.

Unresponsive: a patient whose DASI decreases by 50.9% - 0%.

Worse: a patient whose DASI values increase in relation to the initial DASI.

% DASI variation (X): given by the percentage of improvement within a given period of time

as compared with the initial DASI. The following formula was used:

X (%) = DASI given period – Initial DASI x 100 Initial DASI

Time of occurrence of response: Variable measured by weeks, from the value at the start of

the treatment to the week in which the response to the treatment occurs.

Discontinuance of treatment: considered when the patient did not complete the weeks of study

due to the following reasons:

1. Occurrence of any exclusion criteria

2. Failure to attend the consultation for two weeks on a row

3. Patient does not want to participate in the research anymore

4. No improvement after 6 weeks of treatment with the product

5. Worsening of symptoms

6. Hypersensitivity to the product

7. Association of other drugs during the treatment

8. Discontinuance of treatment due to other reasons

Therapeutic failure: considered when the patient was:

1. Assessed as Worse in two consecutive consultations.

2. Assessed as Worse or Not Responsive at the sixth week of treatment, that is, when the

Week 6 DASI has not decreased by at least 51% in relation to the initial DASI.

Analysis of Results

A characterisation was conducted, by means of graphic methods, of the universe of patients

under study on the basis of a series of a wide range of variables deemed to have a possible

influence on the results of the treatments under study, which were: gender, skin colour, age

groups, lesion location, previous lesion development time, pathological personal and family

history, and this entity’s aggravating factors (food, sweating and environment).

To evaluate the therapeutic effect of both forms of Blue-Cap and Viusid sachets, we

conducted a descriptive analysis of the variables related to the response to the treatment:

- Percentage of clinical response reached by groups under treatment.

- Time of occurrence of the response.

- Analysis of any Side Effects detected in relation with the use of the drugs.

Statistical processing and analysis

The statistical processing and analysis were based on the comparison of both groups in terms

of response variables. The methods applied were the following: descriptive, inferential

(comparison) and graphic.

Results and Discussion

Characterization of the universe of patients under study: Table 1. Age group distribution

Age Females Males Total N % N % N %

2 – 6 mo 1 3.3 1 3.3 2 6.6 7 – 11 mo 2 6.6 1 3.3 3 10.0 1 – 2 yr 1 3.3 2 6.6 3 10.0 3 – 6 yr 4 13.3 6 20.0 10 33.3 7 – 10 yr 9 30.0 3 10.0 12 40.0

Source: CRF

Chart 1. Age group distribution

0

2

4

6

8

10

12

2 - 6 m 7 - 11 m 1 - 2 a 3 - 6 a 7 - 10 a

FemeninoMasculino

The distribution of age groups shows that participating patients were 2-month to 10 year old

children, with predominance in the corresponding age 7-10 (40%), followed by the age 3-6

group (33%), different from what is described in bibliographic references, which states that

this entity affects babies under aged under one year for 50% of patients, and between ages 1

and 5 for 30% of patients. (4)

Table 2. Gender distribution

Gender Frequency %

Female 17 57 Male 13 43 Total 30 100 Source: CRF Chart 2. Gender distribution

1343%

1757%Femenino

Masculino

Fuente: Tabla 2

Prevalence of females (57%) over males (43%, which coincides with available bibliographic

references that state a slight predominance of this disease on females. Wüthrich B. also states

this in his article, specifying that the prevalence in the US ranges between 10% and 12%, with

a slight predominance of females (4.54).

Table 3. Skin colour distribution

Skin colour Frequency %

White 12 40 Mixed-race 13 43 Black 5 17 Total 30 100 Source: CRF Chart 3. Skin colour distribution

1240%

1343%

517%

BlancaMestizaNegra

Fuente: Tabla 3

Most participating patients were mixed-race (43%) followed very closely by white patients

(40%) and a minority of black patients (17%). This coincide with a number of research studies

which highlight the occurrence of atopic dermatitis on all skin colours (8), yet disagrees with

other studies in which black skin predominates (54) —data that could be influenced by the

predominance of mixed-race population in our area.

Table 4. Lesion development time-based distribution

Development time Frequency %

Under 1 month 12 40.0 1 - 4 months 5 17.0 5 - 8 months 2 6.6 9 - 12 months 1 3.3 Over 1 year 10 33.3 Total 30 100.0 Source: CRF Chart 4. Lesion development time-based distribution

12

5

2 1

10

-1

13

5

79

1113

15

Under 1 mo 1-4 mo 5-8 mo 9-12 mo Over 1 yr

Source: Table 4

The distribution of lesion development time was analyse, to find a predominance of

development times under one month for 40.0% of patients, followed by lesions with

development time over one year (33.3%), the latter coinciding with other studies that have

found that this entity features chronic development. (2, 3,4).

Table 5. Lesion location distribution

Location Frequency

Scalp 0

Face 19

Flexures 40

Extensor areas 18

Trunk 9

Generalized 2

Source: CRF

The distribution of lesion locations shows that patient flexure areas were the most affected,

followed by: face, extensor areas and trunk. No lesions were found on scalps, all of which

corresponds with the most commonly affected areas taking into account the age groups that

prevail in this study.

Table 6. Pruritus behaviour.

Pruritus levels Initial check-up Final check-up

N % N % Absent 1 3.3 13 43.0 Occasional 2 6.6 12 40.0 Present 12 40.0 1 3.3 Impertinent 7 23.0 2 6.6 Severe 8 27.0 2 6.6 Total 30 100.0 30 100.0 Source: CRF

As for the clinical markers, twenty-nine out of the thirty patients were affected by pruritus on

the initial check-up, which was occasional for two of them, present in twelve, impertinent for

seven and severe for eight, which corresponds with findings from other studies reviewed (55).

Itchiness diminished with the treatment applied to seventeen patients with pruritus by the time

of final consultation, twelve of which reported occasional pruritus and thirteen did not

reported at all.

Table 7. Distribution based on personal pathological background

Personal pathological background

Frequency %

None 5 16.7 Bronchial asthma 10 33.3 Allergic rhinitis 15 50.0

Source: CRF

Upon analysis of the distribution based on personal pathological backgrounds, we found that

out of 100.0% of children with Atopic Dermatitis, 50% also suffered Allergic Rhinitis and

33.3% Bronchial Asthma, which coincides completely with the theory that almost 80% of

children with Atopic Dermatitis develop Allergic Rhinitis or Asthma —which suggests a

systemic connection between Respiratory Allergy and Atopic Dermatitis. (4)

Table 8. Distribution based on family pathological background

Family pathological background Frequency %

Atopic Dermatitis 7 23.0 Bronchial Asthma 25 83.0 Allergic Rhinitis 17 57.0 Source: CRF The distribution based on family pathological background shows that participating patients

had a predominance of relatives with Bronchial Asthma and Allergic Rhinitis (83.0% and

57.0% respectively), which coincides with findings in other research studies. (56, 57, 58)

Table 9. Distribution by aggravating factors

Aggravating factors Frequency %

Food 17 57.0 Environment 15 50.0 Sweating 9 30.0 Source: CRF Chart 5. Distribution by aggravating factors

Source: Table 9 In relation with the distribution by aggravating factors, we found a predominance of food-

induced factors (57.0%), followed by environment, sweating and stress (50.0%, 30.0% and

20.0% respectively), which coincides with findings in other research studies. (28, 55, 57)

Table 10. Response to the treatment according to Blue-Cap form.

Blue-Cap cream Consultation

1 Consultation

2 Final

Consultation F % F % F %

Clean 0 0.0 2 13.0 4 26.6 Responsive 6 40.0 7 47.0 6 40.0 Unresponsive 9 60.0 5 33.0 4 26.6 Worsening 0 0.0 1 7.0 1 7.0 Total 15 100.0 15 100.0 15 100.0 Blue-Cap gel Clean 0 0.0 1 7.0 5 33.0 Responsive 7 47.0 11 73.0 7 47.0 Unresponsive 8 53.0 2 13.0 3 20.0 Worsening 0 0.0 1 7.0 0 0.0 Total 15 100.0 15 100.0 15 100.0 Source: CRF Chart 6. Distribution based on response to treatment

0

2

4

6

8

10

12

Consu

lt 1

Consu

lt 2

Final C

onsu

lt

Consu

lt 1

Consu

lt 2

Final C

onsu

lt

Blue-Cap cream Blue-Cap gel

Clean Responsive Non Responsive Worsening

Source: Table 10

The analysis of response to treatment on both groups shows 66.6% response from the group of

patients who received Blue-Cap cream, compared with 80.0% of Blue-Cap Gel patients, both

groups with a response to treatment above 51.0%. To mention that patients who responded to

the treatment included four patients (26.6%) that came up clean after using Blue-Cap cream,

and five patients (33.0%) clean thanks to Blue-Cap Gel. Unresponsive patients only included

one who got worse in the Blue-Cap Cream group. We believe that this was due to suffering

repeated Asthma attacks during the Blue-Cap treatment, for which the child received

systemically administered steroids. Upon discontinuance, the child’s dermatological condition

underwent a rebound effect.

Table 11. Time of occurrence of response (weeks)

Blue-Cap cream Consultation 1

2 weeks Consultation 2

4 weeks F % F %

Respondent 6 40.0 9 60.0 Total 15 100.0 15 100.0 Blue-Cap gel Respondent 7 47.0 12 80.0 Total 15 100.0 15 100.0 Source: CRF Chart 7. Time of occurrence of response (weeks)

0%

20%

40%

60%

80%

100%

2 Semanas 4 Semanas

Blue-Cap crema

Blue-Cap gel

Source: Table 11

Analysis of the time of occurrence of response (in weeks) shows that, after two weeks of

treatment, the Blue-Cap Cream group had six Responsive Cases (40.0%), while the Blue-Cap

Gel displayed a similar behaviour, with seven Responsive cases in the (47.0%). Following

four weeks of treatment, we detected nine more Responsive patients in the Blue-Cap Cream

group (60%), and twelve Responsive patients in the Blue-Cap Gel group (80%).

Table 12. Distribution by side effects

Side effects Total

F % Skin irritation 3 10% Total 30 100% Source: CRF Chart 8. Distribution by side effects

10%

90%

Irritation

No reaction

Source: Table 12

Side effects detected were assessed. Two Blue-Cap Cream and one Blue-Cap Gel patients

displayed local irritation. These reactions occurred during the treatment, and it was decided to

discontinue it temporarily. In general, the treatment caused three adverse reactions on three

patients, representing 10.0% of the thirty patients participating in the Blue-Cap study.

Patients who were administered Viusid in sachets did not display any side effects, yet it must

be noted that six out of the thirty patients who underwent said treatment reported an

unpleasant flavour, while another reported diarrhoea and another loss of appetite. Taking into

account this, we would recommend an improvement of the formulation for the purpose of

making it more pleasant to taste and, therefore, to minimise the risk of discontinuance of the

treatment for said reason.

Conclusions

1. The combined Blue-Cap/Viusid treatment was effective on patients with Atopic

Dermatitis.

2. Predominance of females, mixed-raced skin colour and children aged 7-10. The flexural

area was the most common location, and the most frequent lesion development time was

under one month. Allergic Rhinitis was the most frequent personal pathological

background, and Bronchial Asthma the most frequent family pathological background.

The most significant aggravating factors were food and environmental factors.

3. No significant side effects caused by the products were detected.

Recommendations

1. Improve the formulation of Viusid to make it more pleasant to taste.

2. Assess percentage of relapse.

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ANNEXES

Annexe 1

Informed Consent Mr / Mrs:________________________________________________________ Identity Card Number: ____________________________ Being of sound mind, I hereby declare on my own free will that I have been duly informed and that, accordingly, I give my consent to my participation in the medical procedure for treatment of atopic dermatitis using either Blue Cap and Viusid, taking into account that: 1. I have understood the nature and purpose of the procedure 2. I have been given the opportunity to clear my doubts 3. I am satisfied with the information provided 4. I understand that my consent can be revoked any time prior to the start of the procedure 5. I hereby declare that all my medical history data I have provided are true and that I have

not omitted any information that may jeopardise the treatment in any way. Therefore, I hereby declare that I have been duly informed and give my consent to my participation in the proposed treatment. Signed by Patient _________________ Signed by Doctor _______________ City of Havana, on the ____ day of ________________ 200__

Annexe 2

CASE REPORT FORM (CRF)

Clinical Trial

“Effectiveness of Blue-Cap/Viusid in the treatment of Atopic Dermatitis “

INCLUSION

1. Institution’s Data

a) Province: __ __ b) Hospital: __ __ 2. Patient’s General Data

a) Patient’s initials: __ __ __ __ b) Inclusion number: __ __ __ c) Date of inclusion: __ / __ / ____ (dd / mm / yy) d) Age: ___ . e) Gender: 1. Male 2. Female f) Skin colour: W__ M __ B __ g) PH _________________________________________________________ h) FH_________________________________________________________ i) Aggravating factors: ___________________________________________ j) ID code: __ __ __ __ __ (Hospital + Inclusion No.)

3. Verification of Inclusion and Exclusion Criteria Inclusion (One or more negative replies will disqualify the individual for the study)

Yes No

• Age: 2 months-10 years • Signed Informed Consent • Presenting atopic dermatitis ranging between 2% and 35% of the

affected body surface as per the results obtained with the Lesion Location Form.

• Not having undergone any treatment within the previous 2 weeks

�1 �1 �1 �1

�2 �2 �2 �2

Exclusion (One or more affirmative replies will disqualify the individual for the study)

Yes No

• Does not meet one or more inclusion criteria • Presenting dermatopathy other than atopic • Severe or convalescent acute infectious diseases • Atopic Dermatitis with superadded infection

�1 �1 �1 �1

�2 �2 �2 �2

Signed by the Researcher: _______________ Date (day/month/year): ___ / ___ / ____

INITIAL ASSESSMENT

1. Institution’s Data

a) Province: __ __ b) Hospital: __ __ 2. Patient’s General Data

a) Patient’s initials: __ __ __ __ b) Inclusion number: __ __ __ c) ID Code: __ __ __ __ __ (Hospital + Inclusion number)

3. Disease Data

a) Lesion location:

Scalp __

Face: Cheeks __, Chin __, Periorbital __, Peribuccal __, Retroauricular__

Neck__

Flexures __

Limb extensor areas __

Trunk __

Wrists __

Ankles __

Generalized ___

b) Lesion development time:

Under 1 month ___

1 - 4 months ___

5 - 8 months ___

9 - 12 months ___

Over 12 months ___

c) Pruritus (0-4): _

4. Photography a) Picture of lesions taken?: 1. Yes 2. No If yes, please specify: b) Picture taken on: _ _ / _ _ / _ _ (dd / mm / yy) 5. Clinical Assessment

a) Complete this table with the patient’s clinical characteristics.

Clinical Assessment

Head Trunk Affected area(0-6) Affected area(0-6) Erythema (0-4) Erythema (0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4)

Upper Limbs Lower Limbs Affected area(0-6) Affected area(0-6) Erythema(0-4) Erythema(0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4)

b) Total number of locations: _ _ _ c) Initial assessment: DASI results: _ _ _

DASI = 0.1 (Erc + Exc + Sc + Fc + Lc) Ac + 0.2 (Ert + Ext + St + Ft + Lt) At +

0.4 (Erb + Exb + Sb + Fb +Lb) Ab + 0.3 (Erp + Exp + Sp + Fp + Lp) Ap

Signed by the Researcher: ________________ Date (day/month/year): _ _ / _ _ / _ _

Description of lesions

Patient Name and Surname Initials: _ _ _ _ _ General Practitioner: _____________________________________________ Hospital: ____________________ Clinical Record: _ _ _ _ _ _ _ Inclusion No.: _ _ _


FOLLOW UP DURING TREATMENT. CONSULTATION 1

1. Institution’s Data a) Province: _ _ b) Hospital: _ _ 2. Patient’s General Data

a) Patient’s initials: _ _ _ _ b) Inclusion No.: _ _ _ c) ID Code: _ _ _ _ _ (Hospital + Inclusion No.)

3. Evolution data a) Did the patient attend the Consultation? 1. Yes 2. No If yes, please specify: b) Date of Consultation: _ _ / _ _ / _ __ (dd / mm / yy) 4. Clinical Assessment

a) A) Complete this table with the patient’s clinical characteristics

Clinical Assessment Head Trunk

Affected area(0-6) Affected area(0-6) Erythema(0-4) Erythema(0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4)

Upper Limbs Lower Limbs Affected area(0-6) Affected area(0-6) Erythema(0-4) Erythema(0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4) Signed by the Researcher: ________________ Date (day/month/year): _ _ / _ _ / _ _

b) Total number of locations: _ _ _ c) Assessment: DASI results: _ _ _

DASI = 0.1 (Erc + Exc + Sc + Fc + Lc) Ac + 0.2 (Ert + Ext + St + Ft + Lt) At +

0.4 (Erb + Exb + Sb + Fb +Lb) Ab + 0.3 (Erp + Exp + Sp + Fp + Lp) Ap d) The patient is or was:

1. Clean 2. Responsive 3. Unresponsive 4. Worse

e) % change DASI: _ _. _ _% f) Pruritus (0-4): _

g) Received treatment with antihistamines? 1. Yes 2. No

4. Side Effects a) Patient has or has experienced Side Effects? 1. Yes 2. No

(If yes, please complete the Side Effects Form) 5. Discontinuance of Treatment a) Was the treatment discontinued at some stage? 1. Yes 2. No (If yes, please complete the Treatment Discontinuance Form) Signed by the Researcher: ________________ Date (day/month/year): _ _ / _ _ / _ _

FOLLOW UP DURING TREATMENT. CONSULTATION 2



3. Evolution data a) Did the patient attend the Consultation? 1. Yes 2. No If yes, please specify: b) Date of Consultation: _ _ / _ _ / _ __ (dd / mm / yy) 4. Clinical Assessment


Clinical Assessment

Head Trunk Affected area(0-6) Affected area(0-6) Erythema(0-4) Erythema(0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4)


b) Total number of locations: _ _ _ c) Assessment: DASI results: _ _ _

DASI = 0,1 (Erc + Exc + Sc + Fc + Lc) Ac + 0,2 (Ert + Ext + St + Ft + Lt) At +

0,4 (Erb + Exb + Sb + Fb +Lb) Ab + 0,3 (Erp + Exp + Sp + Fp + Lp) Ap

d) The patient is or was: 1. Clean 2. Responsive 3. Unresponsive 4. Worse


5. Side Effects a) Patient has or has experienced Side Effects ? 1. Yes 2. No

(If yes, please complete the Side Effects Form)

6. Discontinuance of Treatment a) Was the treatment discontinued at some stage? 1. Yes 2. No (If yes, please complete the Treatment Discontinuance Form) Signed by the Researcher: ________________ Date (day/month/year): _ _ / _ _ / _ _

FINAL ASSESSMENT


a) Patient’s initials: _ _ _ _ b) Inclusion No.: _ _ _

c) ID Code: _ _ _ _ _ (Hospital + Inclusion No.)

3. Evolution data a) Date of Assessment: _ _ / _ _ / _ __ (dd / mm / yy) 4. Clinical Assessment


Clinical Assessment

Head Trunk Affected area(0-6) Affected area(0-6) Erythema(0-4) Erythema(0-4) Excoriation (0-4) Excoriation (0-4) Dryness (0-4) Dryness (0-4) Cracks (0-4) Cracks (0-4) Lichenification (0-4) Lichenification (0-4)


b) Total number of locations: _ _ _ (Please complete the Lesion Description Form)

c) FINAL ASSESSMENT: DASI results: _ _ _ DASI = 0.1 (Erc + Exc + Sc + Fc + Lc) Ac + 0.2 (Ert + Ext + St + Ft + Lt) At +

0.4 (Erb + Exb + Sb + Fb +Lb) Ab + 0.3 (Erp + Exp + Sp + Fp + Lp) Ap

d) Final Classification:

1. Clean or Virtually Clean 2. Responsive 3. Unresponsive 4. Worse


5. Side Effects a) Patient has or has experienced Side Effects? 1. Yes 2. No

(If yes, please complete the Side Effects Form)

6. Discontinuance of Treatment a) Was the treatment discontinued at some stage? 1. Yes 2. No (If yes, please complete the Treatment Discontinuance Form) 7. Photography a) Picture of the patient taken?: 1. Yes 2. No If yes, please specify: b) Picture taken on: _ _ / _ _ / _ _ (dd / mm / yy)

Signed by the Researcher: _________________ Date (day/month/year): _ _ / _ _ / _ _

DISCONTINUANCE OF TREATMENT



3. Data on Discontinuance of Treatment a) Date de la Discontinuance of Treatment: _ _ / _ _ / _ __ (dd / mm / yy) b) Specify the reasons: Reasons Yes No

Occurrence of an exclusion criteria

�1 �2

Failure to attend the consultation for two weeks on a row

�1

�2

Patient does not want to continue with the treatment

�1

�2

No improvement after 6 weeks of treatment with the product

�1

�2

Worsening of symptoms

�1

�2

Hypersensitivity to the product

�1

�2

Association of other medication during the treatment

�1

�2

Discontinuance of treatment due to other reasons

�1

�2


Side Effects

1. Institution’s Data a) Province: _ _ b) Hospital: _ _

2. Patient’s ID data a) Patient’s initials: _ _ _ _ b) Inclusion No.: _ _ _ c) ID Code: _ _ _ _ _ (Hospital + Inclusion No.)

3. Data on Side Effects

Side Effects Start Date (day / month /

year)

End Date (day / month / year)

Intensity level code

1. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

2. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

3. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

4. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

5. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

6. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

7. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

8. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

9. _ _ / _ _ / _ _ _ _ / _ _ / _ _ _

Intensity level code

1. Slight: No treatment required 2. Moderate: Subsides with medication 3. Severe: Does not subside with medication 4. Very severe: life threatening Signed by the Researcher: _________________ Date (day/month/year): _ _ / _ _ / _ _

4. Treatment of Side Effects

Medication No. of Side

Effects

Dosage Frequency Start date (day / month /

year)

End date (day / month /

year)

1. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

2. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

3. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

4. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

5. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

6. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

7. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

8. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

9. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

10. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

11. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

12. _ _ _ _ / _ _ / _ _ _ _ / _ _ / _ _

Signed by the Researcher: _________________ Date (day/month/year): _ _ / _ _ / _ _

Annexe 3

GUIDELINES FOR COMPLETION OF THE CASE REPORT FORM

1. The questionnaire shall be completed with clear handwriting in capital letters, and preferably with blue or black ink.

2. Provide answers by ticking the boxes with an X. Example: �

3. The lines are for either numbers or letters. Example: _0 1_ , _1 _2

4. Date fields are completed by following the sequence day / month / year. Example: _1 8_ / _1 _2 / _9 _6 (18 December 1996)

5. If the requested data is unavailable, please write NA. Example: _ _ . N_ D_

6. If you need to correct any data, please cross it out with a single horizontal line so the corrected data remains visible. Example: 13 12

7. Write your initials and date by the data crossed out. Example: 13 AR 25 / 12 / 95 12

8. Hour fields will be completed by following the sequence Hour: Minute, and specifying either am or pm. Example: 01: 45 am � pm �

9. Each patient will be provided with their unique ID Code during the development of the research study. This code includes the following numbers and letters: The first two positions from the left are the Hospital’s Code, and the remaining positions are for the Patient’s Inclusion Number. This code will be included in each page of the CRF, and shall be provided at all times. Example: Patient 1 in Hospital Miguel Enríquez shall have the following ID Code: ID Code: M E 001

10. The Patient’s initials will be provided as follows:

The first two positions from the left are for the initials of the patient’s first and second Christian names and the third and four positions for the initials of the first and second surname respectively. If you only have one name, please write 0 on the second position. If you have a hyphenated surname, used only the initial of the first surname. Example: J C P D José Carlos Pérez Dayz 0 J P D José Pérez Dayz J C P D José Carlos Pérez- González Dayz 0 J P D José Pérez- González y Dayz- Gómez Prepositions and articles will not be taken into account when coding surnames.

11. Categories to take into account for classification of the requested information. (The number associated to each category will be written in the CRF).

Pruritus:

No Categories

0 Absent symptom

1 Occasional

2 Present, does not alter sleep, can cause excoriation.

3

Impertinent, increases at night, can cause insomnia, excoriation, lichenification

4 Severe, distressing, keeps the patient awake at night

Affected area:

No Categories

0 Lesion-free area

1 Lesions in 1% - 10% of area





6 Lesions in 91% -100% of area

Erythema, Excoriation, Dryness, Cracks, Lichenification:

No Categories

0 Absent signs

1 Slight expression

2 Moderate expression

3 Intense expression

4 Exceptionally intense expression

Reaction to Treatment:

Clean o Virtually Clean Patient When the DASI’s final value decreases by at least 90% of the initial value

Responsive Patient When the DASI’s final value decreases by 89.9% - 51% of the initial value

Unresponsive Patient When the DASI’s final value decreases by 50.9% - 0% of the initial value

Patient in Worse Condition When the DASI’s final value increases in relation to the initial value

Annexe 4

GUIDELINES FOR CALCULATION OF DASI

(DERMATITIS ASSAY SCORE INDEX) Procedure: 1. Mark the affected zone on the grid drawings following the contour of the grid. 2. Count the boxes corresponding to the affected zone marked in each area (Head, Trunk, Upper Limbs and Lower Limbs, including anterior and posterior sides). Two incomplete boxes are considered for each integer. 3. Look on the following table for the value of the line below corresponding to the sum of boxes per area. This number (#) is used in the DASI formula in the part corresponding to each area.

Affected zone or area

1 - 10% 11 – 30% 31 – 50% 51 – 70% 71 – 90% 91 – 100%

Head 1 - 31 32 - 92 93 - 154 155 - 216 217 - 277 278 - 308

Trunk 1 - 178 179 - 533 534- 888 889 - 1243 1244 - 1598 1599 - 1776

Upper limb 1 - 110 111 - 330 331 - 551 552 - 771 772 - 991 992 - 1101

Lower limb 1 - 174 175 - 521 522 - 869 870 - 1217 1218 - 1564 1565 - 1738

DASI 1 2 3 4 5 6

In the event that the area is not affected, the number (#) of boxes is 0, and the value included in the DASI formula corresponding to said area is 0. DASI formula:

DASI = 0.1 (Erc + Exc + Sc + Fc + Lc) Ac + 0.2 (Ert + Ext + St + Ft + Lt) At + 0,4 (Erb + Exb + Sb + Fb +Lb) Ab + 0.3 (Erp + Exp + Sp + Fp + Lp) Ap where: Er is the erythema severity value Ex is the excoriation severity value S is the dryness severity value F is the crack severity value L is the lichenification severity value

Annexe 5

INCLUDED AND EXCLUDED PATIENT RECORD

a) Province: _ _ b) Hospital: _ _ c) General Practitioner: _________________________________________ Date (day / month / year) Patient’s

initials Included Number

Excluded Reasons*

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

_ _ / _ _ / _ _

*Reasons for Non Inclusion

1. No signed informed consent provided

2. Age: under 2 months or over 10 years of age

3. Having undergone previous treatment

4. Presenting dermatopathy other than atopic

5. Atopic Dermatitis not covering at least 2%, or covering over 35%, of the affected body surface. 6. Severe or convalescent severe acute infectious diseases

7. Atopic Dermatitis with superadded infection

Annexe 6

RESEARCHER’S LOG

Province: ______________________ Hospital: __________________________

ID Code Patient’s initials Patient’s Name Clinical

Record Home Address Telephone

Pictures Before the treatment: After the treatment:

Pictures Before the treatment:

After the treatment:

Before the treatment:

After the treatment:

Before the treatment

After the treatment


After the treatment


After the treatment


After the treatment

Date post:	13-Feb-2020
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