Efficacy And Safety Of Action Of ‘md Applied To The Skin, Versus Placebo In Adults Subjects With Mild Atopic Dermatitis

CLINICAL STUDY PROTOCOL

Efficacy and Safety of Action of “MD Applied to the Skin, Versus Placebo in Adults Subjects with Mild Atopic Dermatitis

Confidentiality statement

The information provided in this document is strictly confidential and is intended solely for the guidance of the clinical investigation. Reproduction or disclosure of this document – whether in part or in full – to parties not associated with the clinical investigation, or its use for any other purpose, the prior written consent of the sponsor is not permitted.

2. PROTOCOL SUMMARY

2.1 PROTOCOL SUMMARY IN ENGLISH

2.2 SYNOPSYS IN NATIONAL LANGUAGE

3. TABLE OF CONTENTS

4. LIST OF ABBREVIATIONS

5. SIGNATURE OF THE SITE INVESTIGATORS

The signatories agree to the content of the clinical study protocol as presented.

Signed copies of this signature page are stored in the sponsor’s study files and in the respective center’s investigator site file.

6. SIGNATURE OF SPONSOR’S MEDICALLY RESPONSIBLE PERSON

The signatory agree to the content of the clinical study protocol as presented.

7. PROJECT TITLE

Efficacy and Safety of Action of “MD Applied to the Skin, Versus Placebo in Adults Subjects with Mild Atopic Dermatitis: A Multicenter, Randomized, Double-Blind, Parallel Group (Dermatostop)

8. PROTOCOL CODE AND VERSION

Protocol code: CNDE27-15

Version

9. INVESTIGATORS

Dermatology, Allergology, and Family Specialist Physicians,

10. PRINCIPAL INVESTIGATORS

To be completed

11. FACILITIES (Name and Address)

Selected sites in Romania

12. OBJECTIVES

Primary objective

The primary objective of the study is to evaluate the safety of

MD by monitoring the Adverse Events

Secondary objective

The secondary objective of the study is to assess the clinical efficacy of the MD in alleviate the symptomatology of mild Atopic Dermatitis

To assess the efficacy of the MD by:

-Using a 4 point (0-3) scale for erythema, pruritus, exudation, excoriation and lichenification –ADSI (Atopic Dermatitis Severity Index)

-SCORAD Calculator at the doctor’s office at the time of the visits.

-Patient chart assessment by POEM –PATIENT ORIENTED ECZEMA MEASURE –recorded every 2 days.

13. STUDY DESIGN

This is a Multicenter, Randomized and Controlled Study.

13.1 STUDY TYPE

This multicenter study will be conducted according to the following design: the included subjects will be administrated the treatment (Product A or product B), once per day topically.

A detailed summary of the protocol is presented in chapter 2.0 Protocol summaries.

14. Background:

Atopic dermatitis (AD) is a chronic inflammatory and pruritic skin disease of unknown clear etiology. A large number of children and adults are affected by it, which can associate a series of allergic diseases.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory, and pruritic, skin disease commonly found in children in the early stages of infancy although less frequently it can onset in later stages of adulthood. Its origin is unknown and can be associated with other atopic diseases (food allergies, allergic rhinitis, asthma) that are connected to immunoglobulin E (Ig E).

That it is the first disease to present in a series of allergic diseases—including food allergy, asthma, and allergic rhinitis, in order—has given rise to the “atopic march” theory, which suggests that AD is part of a progression that may lead to subsequent allergic disease at other epithelial barrier surfaces.[1, 2] 

References

Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. Aug 2010;105(2):99-106; quiz 107-9, 117. [Medline].

Carlsten C, Dimich-Ward H, Ferguson A, Watson W, Rousseau R, Dybuncio A, et al. Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors. Ann Allergy Asthma Immunol. Jan 2013;110(1):24-8.

It is estimated that 60% of the cases occur in the first year of an infant’s life and an 85% onset rate by the age of five.
It appears suddenly as a rash (skin is red warm and tender), located most commonly on the face and neck areas, wrists, creases of the elbows and knees bony protuberances and less frequently in the diaper area, that causes acute itchiness. It is characterized by pruritus, dry skin (xerosis), thickening of the skin (lichenification) and skin lesions.

It is a lifelong condition in over 50% of persons that had AD as childrens, characterized by flaring, with occurrences that cannot be predicted, although environment, climate, stress, nutrition, allergies and personal hygiene seem to play a role.

AD affects roughly 10-20% of children in developed countries and 1-3% of the adults with a higher prevalence amongst Black, Asian and emigrant population, and a lower prevalence in developing countries (3-5%-eg. China and Iran) as recent studies show.

Atopic Dermatitis is considered a multifactor disease linked to such factors as : – hereditary predisposition
– immunological factors (Ig E)
– metabolic imbalances
– endocrine factors
– skin conditions
– aggravating factors (viruses and bacteria and fungi that can further complicate skin lesions)
-asthma
-hay fever

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To date, there is no known specific chemical marker used to diagnose AD, therefore it is done solely by clinical exam, by using Williams’s criteria as:

Laboratory testing are of little help and sometimes a patch test used to identify allergies can prove helpful in identifying allergens. Using a swab to collect infected skin can identify a specific organism that may complicate the clinical picture.

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Treatment of AD is focused on controlling the itching, preventing associated infection from occurring, reducing inflammation, preventing the lesions from spreading, removing dead skin (scales) and making sure the skin stays supple an hydrated.

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It sometimes involves a lifestyle change and puts a financial strain on families compared to that of more severe diseases (eg. diabetes, arthritis).

Patients will often visit their dermatologist during flare-ups, but there is no way of knowing when the next flare will occur.

Prevalence of the disease is on the rise, with recent studies showing numbers as high as 30% in children and 10% in adult population in North America and developed European countries. Mortality is not as issue, but lesions of the skin and, of other epithelial barriers associated with AD allows for an open port of entry for various other pathogens which can lead to severe illnesses.

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15. Clinical Study Endpoints:

15.1 Study endpoints

15.1.1 Primary endpoint

• Occurrence of adverse events: frequency, intensity and relation with the administered treatments during the study period;

• Results of clinical parameters monitored and vital signs examined between pre- and post-study visit.

15.1.2 Secondary endpoint

Efficacy of MD will be assessed through the entire study by using:

-4point (0-3) scale for erythema, pruritus, exudation, excoriation and lichenification –ADSI (Atopic Dermatitis Severity Index)

-SCORAD Calculator at the doctor’s office at the time of the visits.

-Patient chart assessment by POEM–PATIENT ORIENTED ECZEMA MEASURE –recorded every 2 days.

16. STUDY DESIGN:

16.1 Study type

The study is designed as double blind, randomized, parallel.

16.2 Study Documentation and Case Report Form

For each subject enrolled, a CRF will be completed, reviewed and signed by the Investigator.

16.3 Study monitoring

CEBIS International will do study monitoring. CEBIS will generate appropriate Monitoring Reports, retained in the Trial Master File, for each visit performed.

16.4 Quality Assurance Audits

The raw data generated during the course of the study and the clinical study reports will be liable for inspection and quality audit for conformance to this protocol and all the governing SOPs by an auditor from the Quality Assurance Department of the Sponsor and Investigator.

16.5 Confidentiality of data

The data identifying each study subject by name will be kept confidential and will be accessible to the study personnel, Quality Assurance Auditor during audits and if necessary, to the Institutional Ethics Committee and various regulatory agencies.

16.6 Archives

A representative sample of the drug supplies used in the study will be retained at the Clinical Unit. All data generated in connection with this study, together with the original copy of this protocol and the clinical study report will be archived as per current versions of the applicable Standard Operating Procedures.

16.7 Publication policy

Results obtained from this study are property of the Sponsor. In case of publication, the Investigators will be informed and will be free to cooperate as Authors.

16.8 Deviations

All protocol deviations will be appropriately reviewed and documented in the raw data and those, which will affect the integrity of the study, will be reported in the clinical study report. For other deviations their impact on the study will be described.

16.9 Termination of the study

The Sponsor reserves the right to discontinue the trial at any time. Reasons for this termination will be provided to the subjects. The Investigators reserve the right to discontinue the study for safety reasons at any time.

In case the study ends early, the Sponsor must immediately notify the Competent Authorities and Ethics Committee about closing the study, within 15 days after it was stopped, with the clear explanation of the causes and presenting any existent follow-up safety measurements taken.

17. MEDICAL DEVICES INVESTIGATED

17.1 Composition of studies Medical Device:

To be completed based on MD Leaflet

17.2 Composition of Placebo

To be completed based on Placebo Leaflet

17.3 IMP Handling, Storage and Accountability Procedures

Investigational medical products will be supplied in the appropriate package deemed to maintain the integrity of the products. The Investigator or the person designated by the investigator will be accountable for the administration of the study products and for return of unused drug products, at each investigational place.

17.4 Posology. Dosage

The patients will be instructed to administrate product A or B for 30 days consecutive days. The treatments (Product A or Product B) will be administrated by topical route every day according to the leaflet of each product:

17.5 Drug-drug interaction

The investigated products are medical devices, containing no medicinal substances.

18. STUDY POPULATION

Dermatologist specialist physicians at individual cabinets will recruit the subjects. Adequate number of subjects will be selected and will undergo a standardized screening.

18.1 Detailed description. Selection of subjects

48 subjects, in two groups of 24 adults between 18 and 65 years of age, Caucasian race, suffering by mild atopic dermatitis will be selected on the following inclusion and exclusion criteria which will be documented in the CRF.

18.2 Clinical assessment

Medical histories and demographic data (including subject’s initials, date of birth), medication use will be recorded. Each subject will undergo local physical examination.

Only the subjects that fulfill the inclusion criteria will be enrolled in the study.

18.3 Inclusion Criteria

Adults between 18 and 65 years

Caucasian race

Willing to sign an Informed Consent Form

Diagnosis of AD by GP, Family Doctor, Allergology Specialist, Dermatology Specialist using Williams Criteria

Had consultation for AD complains within last 3 months or repeated their prescriptions for AD treatment in the last 3 months.

SCORAD Index- mild 0-24

18.4 Exclusion Criteria

The patients fulfilling any one of the following criteria will be not eligible for the admission to the study:

Pregnant women or breastfeeding;

Unwilling to sign the informed consent form;

Allergy to one of the product ingredients;

Impossibility to come at the study visits.

Health status not allowing participating in the study;

Moderate and Severe Atopic Dermatitis

(SCORAD Score (moderate 25-50, and severe 51-103)

Receiving antibiotics or other topical or oral therapy daily for Atopic Dermatitis for a flare up.

Eruption by viral or bacterial infection

Skin Ulceration

Vaccination

Patients receiving phototherapy or radiation therapy

Taking antihistamines within one week before randomization

18.5 Restrictions and Prohibitions

18.5.1 Medication

Patients will not be allowed to take any medicine or product that may interact with the study treatments during the entire study period. If subject requires to such products, they will be excluded from the evaluation and statistical analysis.

18.6 Criteria for discontinuation or removal of subjects from the study

The Investigator may withdraw a subject from the study for any of the following reasons:

i. The subject suffers from significant inter-current illness or undergoes surgery during the course of the study.

ii. The subject experiences an adverse event, and withdrawal would be in the best interest of the subject.

Details of reasons for withdrawal of subjects will be recorded and reported.

The Investigator based on the subjects’ medical history and health status at the moment of withdrawal/drop-out, in order to ensure the welfare of the subject, will decide the extent of the follow-up safety procedures.

19. STUDY PROCEDURES

Subjects will attend 5 visits:

Baseline visit (Visit 1)

Visit 2 after 9 days of treatment

Visit 3 after 19 days of treatment

Visit 4 after 30 days of treatment

Baseline visit (Visit 1): during the baseline visit the following will be collected:

Informed Consent Form;

Demographic data: age, gender.

Medical history: previous diseases or any previous important medical condition.

Clinical status (related to symptoms of

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Visit 2, Visit 3 and Visit 4 (at days and respectively days from treatment initiation): Clinical evolution of the patient will be assessed daily based on the diary, through the evolution of the following clinical symptoms and signs: (Scale)

A 7-point Likert scale (1-very much worse, 2-much worse, 3-somewhat worse, 4-same condition, 5-somewhat better, 6-much better, 7-very much better) will be used for each symptom. At each visit the investigator will discuss with the patient regarding the daily clinical status based on the diary. Based on the diary the investigator will collect clinical relevant data into the CRFs.

Telephone follow-up will be done by the investigator in order to ensure the clinical condition of the patient.

20. ADVERSE EVENTS AND EMERGENCY PROCEDURES

Subjects will be informed to bring to the notice of the medical personnel any adverse events that may occur during their participation in the clinical study.

A physician, either at the site of investigation or at a specialized medical unit, will do treatment of any adverse events.

All adverse events and treatment administered will be recorded in the clinical study report. Adverse events experienced by subjects will be reported as per the applicable standard operating procedures and followed until the events have subsided. The study may be suspended or terminated depending on the seriousness of the adverse effects.

20.1 Notification of serious adverse events

Any adverse reaction or abnormal value in the laboratory exams that is defined as Serious Adverse Events (SAEs), and which occurs during this study, will be immediately communicated by the Investigator to CEBIS International Ltd. Using the e-mail address: [anonimizat] who will immediately notify the Sponsor’s representative – to take the necessary steps in reporting to the relevant authorities.

20.2 Classification Method for Adverse Events and Serious Adverse Events

20 .2.1 Definitions (according to MEDDEV 2.7 guidelines)

An adverse event/experience (AE) is any unwarranted medical occurrence in a patient. For the purposes of this document, this is intended to include any adverse event whether device related or not.

All adverse events will be recorded on the case report forms provided; a description of the event, intensity, duration, any action (e.g. treatment and follow-up tests) and the outcome should be provided along with the investigators assessment of the relationship to the trial treatment.

20.2.2 Adverse Event (or Adverse Experience)

Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other persons whether or not related to the investigational medic al device.

NOTE 1: This includes events related to the investigational device or the comparator.

NOTE 2: This includes events related to the procedures involved (any procedure in the clinical investigation plan).

NOTE 3: For users or other persons this is restricted to events related to the investigational medical device.

Discrete episodes of chronic conditions occurring during a study period will be reported as adverse events in order to assess changes in frequency or severity. Adverse events will be documented in terms of a medical diagnosis (es). When this is not possible, the adverse event will be documented in terms of signs and symptoms observed by the investigator or reported by the subject at each study visit. Pre-existing conditions or signs and/or symptoms (including any which are not recognized at study entry but are recognised during the study period) present in a subject prior to the start of the study will be recorded on the Medical History form within the subject's CRF.

21. ETHICAL CONSIDERATIONS

21.1 Basic Principles

The study will be performed according to the revised Declaration of Helsinki for biomedical research involving human subject, the rules of Good Clinical Practice (GCP) of the European Community, CPMP (CPMP/ICH/135/195; ICH Topic E6), of UNI EN ISO 14155:2012 and the Guidelines MED DEV 2.7/1 rev 3, MED DEV 2.7/3, MED DEV 2.7/4.

21.2 Independent Ethics Committee

This protocol, the corresponding informed consent form (ICF) and any other information provided to study subjects will be reviewed by an Institutional Ethics Committee and the study subjects will not be screened until the Ethics Committee has approved the protocol and the ICF, as submitted or with modifications. The Ethics Committee is constituted and operates in accordance with the Principles and requirements described in the ICH E6 (R1) (CPMP/ICH/135/95). A copy of the clinical study report will be provided to the Institutional Ethics Committee in accordance with the current regulations.

21.3 Informed Consent

The Investigator will inform the subjects about the study through an oral presentation regarding the purpose, procedures that will be carried out, potential hazards and the rights of the subjects. All subjects will be required to understand and sign a consent form summarizing the discussion before study initiation and screening examination. The original copy of the informed consent form will be retained in the Investigator’s Trial Master File.

22. ACCEPTANCE CRITERIA OF PROTOCOL DEVIATION

All protocol deviations will be appropriately reviewed and documented in the raw data and those, which will affect the integrity of the study, will be reported in the clinical study report. In addition, deviations from original pharmacokinetic and statistical evaluation plan will be justified in the clinical study report.

23. STATISTICAL METHODS/DATA ANALYSIS:

23.1 SAMPLE SIZE DETERMINATION

23.2 STATISTICAL METHODS

References

Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. Aug 2010;105(2):99-106; quiz 107-9, 117. [Medline].

Carlsten C, Dimich-Ward H, Ferguson A, Watson W, Rousseau R, Dybuncio A, et al. Atopic dermatitis in a high-risk cohort: natural history, associated allergic outcomes, and risk factors. Ann Allergy Asthma Immunol. Jan 2013;110(1):24-8.

*Watson and Kapur Allergy, Asthma & Clinical Immunology 2011 7(Suppl 1):S4   doi:10.1186/1710-1492-7-S1-S4