Safety and Efficacy of the Full Face Applications of Variable Doses of a Commercial Botulinum Toxin Type a (Dysport®)

Phase Iv Study On The Safety And Efficacy Of The Full Face Applications Of Variable Doses Of 125 To 250 Units Of A Commercial Botulinum Toxin Type A (Dysport®)

This is an open-label and phase IV study of full face injections of variable doses of botulinum toxin type A (BT-A). As it is an open-label and not blind study, both investigator and subjects will know the injection local and doses of the study drug. Patients will be randomized into 3 different groups. Each group will receive a specific dose according with the indication evaluated by the investigator. Six visits will be schedule in this study.

4.2 Methodology

4.2.1 Patient evaluation After providing written informed consent, subject's eligibility will be assessed at a Screening Visit. The subject's general medical history will be recorded. This includes demographic data, history of surgical and cosmetic procedures, dermatological assessment, physical examination, and prior concomitant medications. A pregnancy test will also be performed.

4.2.1.1 Severity of wrinkles

One sub-investigator will rate the wrinkles with the following validated severity scales for the main areas of the face at Baseline, Week 4, Week 8, Week 16 and Week 24:

• Clinical 0-3 score for standardized assessment of facial wrinkles in the glabella area (from GLADYS study)
• Photometric Atlas for the Assessment of Crow's Feet Severity
• Facial Wrinkle Scale, for forehead lines (Carruthers A, et al. Dermatol Surg. 2003;29(5):461-7)

4.2.1.2 Standard set of photographs will be taken

At Screening , 2, 3, 4 and 5 visits, photographs will be taken:

All the photographs will be taken in a standardized photographic mode with fixed position of the camera. A guideline with examples of standardized photos with delimit standardized positions will be provided to the person responsible to take the photos.

In the photographs, each research subject will be identified by a tag containing a reference to the study, the number of the research subject and the control date. The research subjects should wash their faces before the photographic procedure to remove excess oil and all make up will be removed. All the pictures will be taken at the same room and under same parameters.

The photograph set consist of

• Full face frontal view relaxed;
• One set of photographs relaxed and contracted of each indication that patient will be or was treated in this study.

At the end of the study, two independent evaluators (dermatologists) will assess before and after pictures in a blinded manner. This evaluation will be done to assess the efficacy of BT-A in the injected areas not assessed by the scales.

4.2.3 Groups of treatment

Subjects will be assigned to one of the three following treatment groups, according with the total dose received in visit 1:

• Group 1: 30 subjects who received 125 to 170 U of BT-A (Dysport®)
• Group 2: 30 subjects who received 171 to 210 U of BT-A (Dysport®)
• Group 3: 30 subjects who received 211 to 250 U of BT-A (Dysport®)

4.2.4 Reconstitution of the study product and Treatment Administration An independent, experienced and registered pharmacist will be the assigned to carry through the reconstitution of the products. She will prepare the dilutions and the syringes of the product (DYSPORT®) immediately prior to the injections.

The dilutions of DYSPORT® 500 units per vial will be made with 2 mL of 0.9% sterile saline, using 3 mL syringes and a 21 gauge needle, giving a concentration of 250 units/mL or 2.5 units/0.01 mL of the reconstituted product.

An experienced dermatologist in the use of botulinum toxins (principal investigator - DH) will perform all the injections according to the indications and total number of units that will be injected according to the treatment plan, which aims to obtain the best results. She will only perform the injections and will not participate in other phases of this study.

The application of the BT-A will be made with Becton, Dickinson and Company (BD) Ultra-fine II 0.3 cc syringes, with a 29 gauge needle, 0.5 cm in length (short needle).

Immediately after the application, the side effects will be verified and if needed, will be registered and managed.

Inclusion Criteria:

1. Written Informed Consent;
2. Subjects aged between 30 and 60 years;
3. Skin Fitzpatrick Phototypes I to VI;
4. Subjects that never received BT-A or who had previous injections of BT-A in no more than one third of the face with in the last 6 months;
5. Subjects presenting at least two indications for treatment with BT-A in each third of the face;
6. Medical history and physical examination which, based on the investigator's opinion, do not prevent the patient from taking part in the study and use the product under investigation;
7. Subjects of childbearing age should present a negative urine pregnancy test (instant test) at baseline and should be using an effective contraceptive method (oral or injectable contraceptive, for at last three months, and use of preservative; subjects with: hysterectomy, oophorectomy or tubal ligation);
8. Availability of the patient throughout the duration of the study (24 weeks);
9. Subjects that agree not to undergo other cosmetic or dermatological procedures during the study;
10. Subjects with sufficient schooling and awareness to enable them to cooperate to the degree required by the study protocol.

Exclusion Criteria:

1. Pregnant women or women intending to become pregnant during the study;
2. Subjects participating in other clinical trials;
3. Presence of scars on the face that may interfere with the result of study;
4. Subjects with neoplastic, muscular or neurological diseases;
5. Concurrent use of treatments that affect neuromuscular transmission, such as curare-like depolarizing agents, lincosamides, polymyxins, anticholinesterases affecting the striated muscle and aminoglycoside antibiotics.
6. Subjects with inflammation or active infection in the face;
7. Subjects with a history of sensitivity to the components of the formula;
8. Subjects with prior history of eyelid ptosis; marked facial asymmetry, excessive dermatochalasis, deep dermal scarring or thick sebaceous skin.
9. Subjects presenting myasthenia gravis, Eaton-Lambert Syndrome and motor neuron diseases;
10. Subjects with coagulation disorders or using anticoagulants;
11. Subjects with known systemic autoimmune diseases;
12. Subjects clinically diagnosed anxiety disorder or any significant psychiatric disorder (e.g. depression) that, in the opinion of the Evaluator, might interfere with the Subject's participation in the study;
13. Subjects with a history of medical treatment non-adherence or showing unwillingness to adhere to the study protocol.