in vivo evaluation and comparison of the efficacies of … · the utilization of any other...

SPINCONTROL ASIA Co., Ltd. 483, 485 Soi Ladprao 101 Ladprao Rd., Wangthonglang, Wangthonglang, Bangkok 10310, THAILAND October 2007

CONFIDENTIAL STUDY REPORT Ref.: C03-PF02-LP-MI07(V01)

IN VIVO EVALUATION AND COMPARISON OF THE EFFICACIES

OF TWO WHITENING PRODUCTS BY CHROMAMETRY: A DOUBLE-BLIND PLACEBO-CONTROLLED SPLIT-FACE STUDY

REFERENCES OF THE TEST PRODUCTS:

Product W1 (active) versus Product W4 (placebo)

Study sponsor:

LIPOTEC C/Isaac Peral 17,

Poligon Industrial Cami Ral, 08850 Gavà, Barcelona, SPAIN

Spincontrol Asia Co., Ltd. 2/23 C03-PF02-LP-MI07-C03-RA(V01)

CONTENT

1. SITE OF EXPERIMENTATION, PARTICIPANTS ................................................... 4 1.1. SITE OF EXPERIMENTATION............................................................................................... 4 1.2. STUDY SPONSOR............................................................................................................... 4 1.3. STUDY MONITOR.............................................................................................................. 4 1.4. INVESTIGATOR.................................................................................................................. 4 1.5. STUDY MANAGER............................................................................................................. 5 1.6. TECHNICIANS.................................................................................................................... 5 1.7. QUALITY ASSURANCE ...................................................................................................... 5

2. SUMMARY OF THE STUDY ........................................................................................ 6 2.1. OBJECTIVE........................................................................................................................ 6 2.2. POPULATION..................................................................................................................... 6 2.3. STUDY DESIGN.................................................................................................................. 6 2.4. STUDY SCHEDULE AND DURATION.................................................................................... 6

3. MATERIALS AND METHODS..................................................................................... 8 3.1. SELECTION OF THE SUBJECTS............................................................................................ 8

3.1.1. Inclusion criteria ...................................................................................................... 8 3.1.2. Exclusion criteria ..................................................................................................... 9 3.1.3. Proscriptions and restrictions .................................................................................. 9

3.2. DESCRIPTION OF THE PRODUCTS....................................................................................... 9 3.3. MODALITIES OF UTILIZATION OF THE PRODUCTS, RANDOMIZATION................................ 10 3.4. CUTANEOUS ACCEPTABILITY, ADVERSE EVENTS............................................................. 11 3.5. WITHDRAWAL FROM THE STUDY .................................................................................... 11 3.6. DISCONTINUANCE OF THE STUDY ................................................................................... 11 3.7. STUDY DESIGN................................................................................................................ 12 3.8. CHROMAMETRY MEASUREMENTS ................................................................................... 12

3.8.1. Principle ................................................................................................................. 12 3.8.2. Measurements......................................................................................................... 13 3.8.3. Evaluation parameters ........................................................................................... 13 3.8.4. Interpretation of the chromametry parameters ...................................................... 14

3.9. EXAMINATION SCHEDULE............................................................................................... 14 3.10. DATA ANALYSIS AND STATISTICS ................................................................................. 15

4. ETHICAL AND LEGAL CONSIDERATIONS ......................................................... 16

4.1. STUDY PERSONNEL ......................................................................................................... 16 4.2. ARCHIVING OF THE DATA ............................................................................................... 16 4.3. ANONYMITY OF THE SUBJECTS ....................................................................................... 16 4.4. CONSENT TO PARTICIPATE IN THE STUDY........................................................................ 16 4.5. CONFIDENTIALITY .......................................................................................................... 17


4.6. QUALITY ASSURANCE .................................................................................................... 17 4.7. REGULATIONS ................................................................................................................ 17 4.8. PRACTICAL CONSIDERATIONS......................................................................................... 17

5. RESULTS........................................................................................................................ 18 5.1. PROTOCOL ADHERENCE .................................................................................................. 18 5.2. DESCRIPTION OF THE STUDY POPULATION ...................................................................... 18 5.3. COMPLIANCE OF THE SUBJECTS ...................................................................................... 19 5.4. CUTANEOUS ACCEPTABILITY, TOLERANCE ..................................................................... 20 5.5. CHROMAMETRY RESULTS ............................................................................................... 20

5.5.1. After 1 month .......................................................................................................... 20 5.5.2. After 2 months ........................................................................................................ 21

6. CONCLUSION............................................................................................................... 23

APPENDICES:

Appendix 1: Study population Appendix 2: Monitoring of the test products’ utilization Appendix 3: Chromametry results at T+1 month Appendix 4: Chromametry results at T+2 months Appendix 5: Copy of the protocol


1. SITE OF EXPERIMENTATION, PARTICIPANTS

1.1. Site of experimentation

SPINCONTROL ASIA Co., Ltd. 483, 485 Soi Ladprao 101, Ladprao Road, Wangthonglang, Wangthonglang, BANGKOK 10310, THAILAND Phone: (+662).370.2688, 370.2589, 370.2740 Fax: (+662).370.2418 E-mail: [email protected]

1.2. Study Sponsor

LIPOTEC SA C/Isaac Peral 17, Poligon Industrial Cami Ral, 08850 Gavà, BARCELONA, SPAIN

1.3. Study Monitor

Mrs. Montserrat MANGUES Documentation and Regulatory Affairs Manager

Cosmetic Division, LIPOTEC SA Phone: (+34).93.638.8000 Fax: (+34).93.638.9393 E-mail: [email protected]

1.4. Investigator

Mr. Fabrice PERIN Manager – Ph.D. SPINCONTROL ASIA Co., Ltd. Phone: (+662).376.0929 E-mail: [email protected]


1.5. Study Manager

Ms. Paweena PUNGPOD Technician - B.Sc. of Biology SPINCONTROL ASIA Co., Ltd. E-mail: [email protected]

1.6. Technicians

Mr. Kamolchai SAETUN Technician - B.Sc. of Microbiology SPINCONTROL ASIA Co., Ltd. Ms. Jadesadaporn RUNGCHAROEN Technician - B.Sc. of Agricultural Industry SPINCONTROL ASIA Co., Ltd.

1.7. Quality Assurance

Mrs. Christine PERRIER Quality Assurance Manager SPINCONTROL 238, rue Giraudeau, 37000 TOURS, FRANCE

Ms. Jutatip BOONGIRD Quality Auditor SPINCONTROL ASIA Co., Ltd.


2. SUMMARY OF THE STUDY

2.1. Objective The objective of this study was to evaluate and to compare the in vivo effects of two whitening products on healthy Asian female subjects. The evaluation was performed using:

Chromametry (measurement of the color of the skin with a chromameter CR-300®,

Minolta, Japan).

2.2. Population Twenty (+2) healthy Asian female subjects, 18-65 years old, all skin types, were selected for this study.

The selection was done according to the inclusion/exclusion criteria listed in paragraph 3.1.

2.3. Study design Randomized double-blind study; Comparative test (placebo-controlled split-face study); Subjects served as their own references.

2.4. Study schedule and duration The study began on May 30, 2007 and ended on July 27, 2007. Evaluations were carried out according to the schedule presented below: Scheduled Procedures:

T0 T+1 month T+2 months Dates 30/05 and

01/06/07 28-29/06/07 26-27/07/07

Chromametry End of the

study


Intermediate results (at T+1 month) were given to the Study Monitor for July 18, 2007. Final results were given to the Study Monitor for August 08, 2007. The final study report was sent for October 17, 2007.


3. MATERIALS AND METHODS

3.1. Selection of the subjects Spincontrol Asia’s subjects’ panel is composed of subjects selected on the basis of a questionnaire filled in on a computer prior to the study that provides details of their medical history and possible allergies, skin-care and make-up habits, as well as a certain amount of administrative information. The recruitment and selection procedures are elaborated in order to guarantee that the subjects receive all possible information about the aims of the study and the consequences of their participation. This recruitment procedure includes: A preliminary interview during which the following points are explained to the subjects:

the study’s modalities, its practical considerations, possible emolument, as well as any possible cosmetic benefits, inconveniences or potential risks;

The information form which is specific to the study, including all essential information is then read;

The consent form is read, approved, and signed by the subjects to substantiate the fact that they freely accept the conditions of the study which have been described to them;

This consent form which is filled in freely and intentionally by the subjects after it has been fully explained to them, in the event of any claims for damages, enables them to benefit from the terms of the insurance policy taken out by the study sponsor.

The subjects recruited for the study were selected under the supervision of the investigator, on the basis of the inclusion/non inclusion criteria listed below. A selection of 20 subjects was made for this study. In case subjects withdrew from the study, 2 additional subjects were included. The results given include all of the present and assessable subjects at the end of the study.

3.1.1. Inclusion criteria

The study was conducted on subjects who fulfilled the following criteria: Asian; Healthy; Female; 18-65 years old; Not using whitening/lightening/anti-dark spots products during the 6 weeks prior to the

beginning of the test; Available for the entire study duration (2 months); Motivated to freely participate in the study;


Without any skin hypersensitivity or allergy to cosmetic products; Not pregnant or not breast-feeding a child and committing herself not being pregnant

during all the study; Not having changed her cosmetic habits since at least 15 days; Not having used any treatments (medicinal, hormonal, dermatological) in the past 2

months; Not being in a non-inclusion period for the studied areas, at the beginning of the study,

because of an other previous cosmetic, dermatological or medical test; Having a healthy skin on the face (free of psoriasis, erythema, edema, scars, wounds); Being willing to follow the full products application procedure.

3.1.2. Exclusion criteria

Failing to meet the inclusion criteria listed above; Simultaneously participating in different biomedical research projects offering no direct

individual benefit and participating in any other studies while on this one; Non-respect of the non-inclusion period during which the subject cannot participate in any

other biomedical research projects offering no direct individual benefit; Having participated in skin or peri-ocular tolerance testing during the past two weeks

and/or in sensitization trials within the past four months; Individuals sentenced to imprisonment by a court decision or in need of urgent care due to

serious illness; Minors as well as individuals of age who are wards of the court, or mentally or physically

handicapped individuals insofar as the study can be undertaken in some other manner; Anyone who has any dermatological disease(s), or any other acute or chronic diseases; The refusal to give her assent by signing the informed consent form.

3.1.3. Proscriptions and restrictions The use of aspirin or products containing aspirin, anti-inflammatory medication or anti-

histaminic agents, or any treatment using corticosteroids taken orally, was proscribed during the entire duration of the study;

The utilization of any other whitening/lightening/anti-dark spots products on the face was proscribed during the entire duration of the study;

Exposing herself intentionally to the sun or making any UV was proscribed during the entire duration of the study.

3.2. Description of the products The test products were supplied free of charge by the study sponsor. The products were creams, packaged in 80 grams jars. One product was the active sample. One product was a placebo. The study sponsor was in charge of products manufacturing and packaging.


He was responsible for products identification, purity determination, composition, innocuousness, and any other characteristics of each product to be tested prior to the beginning of the study. The study sponsor supplied a non-toxicity certificate for the tested products.

References of the test products:

Product W1 (batch U18E1-07) versus Product W4 (batch U21E3-07) Remark: W1 was the active product and W4 was its placebo. The study sponsor was responsible for supplying the exact amount of products needed to undertake the testing. For this study, the study sponsor agreed to supply: The appropriate quantity of products required to treat all the subjects; A sufficient quantity of products for any additional subjects participating in the study; One product unit per reference and per batch to be retained in the Reference Products

Cabinet. Products were stored at ambient temperature, protected from contacting with air, light, heat and moisture.

3.3. Modalities of utilization of the products, randomization Each product was applied on one randomly selected half-face twice daily, in the morning and in the evening, over a 2 month- period, by the subjects themselves. Products were randomly assigned to the subjects in a manner which was balanced for right and left half-faces across the panel. This randomization was undertaken by a software designed for this purpose. Subjects had to prevent themselves from any solar exposure or UV exposure during the study, apart from their usual habits. They were instructed to use a sunscreen (SPF 15 minimum) if they could not avoid occasional exposure. Test products weights were measured at each visit in the test center to ensure that the appropriate amounts of test materials were being used. Subjects were instructed not to use any other types of cosmetic creams or products on the face (in particular other whitening/lightening/anti-dark spots products) during the entire study. A subject declaration form was distributed to each subject at T0, checked at each visit and collected back at the end of the test in order to monitor the compliance of the subjects regarding to the products application.


3.4. Cutaneous acceptability, adverse events Any major or unexpected adverse effects immediately prompted the subject showing any intolerance whatsoever to stop application of the product(s) (an adverse event was defined as any expression of unwanted symptom felt or observed by the subjects, related or unrelated to the tested product). Any major adverse effect had to be reported to the study monitor within 48 hours and confirmed in writing within three days. Any incident occurring during the study had to be recorded by the study manager in the study file. The nature, severity, date of appearance, duration, end date, any symptom assessment and any possible treatment had to be described in the observation records as well as the possible cause of the unexpected effect. In case of emergency, the investigator had to initiate the appropriate medical treatment. Despite such a treatment, should severe skin problems have developed following application of the test products, the study sponsor had to take responsibility for the financial cost of the dermatological or medical follow-up of the subject in question.

3.5. Withdrawal from the study A subject accepted into the study might have been withdrawn or considered to have “dropped-out” if: A side effect attributable to the product(s) was judged severe by a dermatologist or a

physician; The subject developed a systemic illness (without being related to the product(s) used in

the study but occurring during the study) and had to take contraindicated medication which was likely to influence the test measurements;

The subject did not respect the protocol. The subjects were entitled to drop out of the study at any time if they so desired (should this have occurred, the study manager had to determine the reasons to know if it was linked to the study or not).

3.6. Discontinuance of the study The study sponsor might have halted the study at any time for one of the following reasons:

Impossibility of recruiting enough subjects; Protocol violations; Incomplete or imprecise data.

The investigator might also have interrupted the study at any time in case of:

Serious skin problems that involved risks to the subjects; should such a problem have

arisen, the study sponsor would have been notified promptly.

3.7. Study design This study was carried out as a double-blind, split-face test and neither the participating

subjects nor the technicians in charge of data collection and evaluations were aware of the type of product (active or placebo) being applied on each half-face;

This was a comparative placebo-controlled study (active versus placebo). Results from the skin treated with the active product were compared to those from the skin treated with the placebo product;

The subjects served as their own references.

3.8. Chromametry measurements Localization of the measurement areas and their locations at the different moments of the kinetics had to be the most rigorously reproducible. The different measurements were done on the left and right cheekbones, for each subject, on sites defined using a gabarit (a transparent overlay used to map the cutaneous features to help us to relocate precisely the measuring sites during all the study). The localizations of the measuring sites were copied out on the observation record.

Figure 1: Illustration of the localization of the treated and measured site on the right cheekbone.

3.8.1. Principle The chromametry principle consists in simulating the perception of colors with the human eye. Chromameters use the tristimulus sensitivity that measures light so as to correspond to the human eye sensitivity. The concept of the tristimulus XYZ values comes from the theory according to which the perception of colors by the eye is made through 3 components (red, green and blue) and all the colors are perceived as a blending of these 3 colors. The Commission Internationale de l’Eclairage (C.I.E.) defined in 1931 a standard observer possessing the functions with the blending of x (λ), y (λ) and z (λ) that enables the calculation of tristimulus values. Tristimulus chromameters are made of a control unit and of a measurement headline. The headline measurement has a light with a pulsed xenon arch lamp which gives out an intense Spincontrol Asia Co., Ltd. 12/23 C03-PF02-LP-MI07-C03-RA(V01)


white light covering the whole visible spectrum (standard light). To compensate any difference of light provided by the pulsed xenon arch lamp, the headline contains a double beam system with a return coupling that measures at the same time the incident light and the reflected light. The color of the reflected light is analysed by 3 high-sensitive silicium photocells which are filtered to equal the curves of the standard observer of the CIE for the primary colors: blue (450 nm), green (550 nm) and red (610 nm). Three other identical filtered photocells are used for the back control system. Thus the photodiode system stimulates the answer of the human eye-brain system. Colors can be classified by their hue, luminosity and saturation. Any color can therefore be characterised in a space where geometric co-ordinates can help to determine brightness, dominant coloring and saturation level. Several spaces of different colors exist, mathematic links making possible the conversion of the co-ordinates from one to another. In the color space L*a*b*, L* expresses brightness on a scale ranging from 0 for the black to 100 for the white. Hue and saturation are expressed by the combination of the chromaticities a* and b*.

3.8.2. Measurements The material used for this study was a chromameter CR-300® (Minolta, Japan). This apparatus is a tristimulus color analyser, made up of a headline associated with a DP-301 calculator. The headline carries out the measures over an 8 mm diameter area and uses a diffuse light with a pulsed xenon arch lamp D65, as well as a sample reading of 0° (specular component included). Before each measurement time, the chromameter was calibrated on a white ceramic plate, provided by the constructor and usually calibrated by this latter. Measurements were performed after a 20 minute- period of rest in a controlled environment (20-24 °C, 40%<RH<60%). At each time of the kinetics and for each side (left and right half-face), 5 acquisitions were made. These 5 measurements were rigorously made at the same location at each time. The results were expressed in the color space L*a*b* (L*: luminance; a*: red-green axis; b*: yellow-blue axis). Measurements were performed throughout the study on the treated and placebo sites (at T0, T+1 month, and T+2 months).

3.8.3. Evaluation parameters The following parameters were used to evaluate the in vivo effects of the tested products on the color of the skin: L* (Luminance) which represents the relative brightness from total darkness (L*=0) to

absolute white (L*=100); a* (red-green color axis); b*(yellow-blue color axis).

Mean values from 5 successive measurements were calculated.


Then from these three co-ordinates were calculated the following parameters: ΔL*, Δa*, Δb*, and ΔITA° between T0 and each of the following time points. Where ITA° = Arctg [(L*-50)/b*].(180/π) is the Individual Typological Angle. All these parameters were determined for the two measured sides of the face.

3.8.4. Interpretation of the chromametry parameters

The best description of a whitening effect is given by combining the L* and b* parameters, as described above, in the so-called Individual Typology Angle ITA° (Petit L, Pierard GE. Skin-lightening products revisited. International Journal of Cosmetic Science, 2003; 25: 169-181). Therefore L* and ITA° were considered for the assessment of the whitening-lightening effect, the more the skin is light, the more the L* and ITA° values are high.

3.9. Examination schedule The effects of the products were evaluated over a 2 month- period. The scheduled measurement procedures were as follows: At T0 (Baseline evaluation before the use of the products): Reception, reading and signature of the consent form; Checking of the inclusion/non inclusion criteria and of the quality of the skin on the face; Acclimatization during 20 minutes; Measurements of skin’s color on the measuring sites (1 site per treated half-face) using the

chromameter CR-300®; Weighing of the test products; Distribution of the test products, of the Subject Declaration form (monitoring of

compliance of treatments between T0 and T+2 months) and of the Information notice. At T+1 month: Acclimatization during 20 minutes; Checking of the instructions and of the quality of the skin on the face; Interview about the subject’s tolerance of the products; Weighing of the test products; Measurements of skin’s color on the measuring sites using the chromameter CR-300®.

At T+2 months: Acclimatization during 20 minutes; Checking of the instructions and of the quality of the skin on the face; Interview about the subject’s tolerance of the products; Collecting of the remaining test products and of the subject declaration form; Weighing of the test products; Measurements of skin’s color on the measuring sites using the chromameter CR-300®; End of the study.


3.10. Data analysis and statistics Mean values (+/- standard deviation) were calculated, as well as variations of the parameters relative to T0 values (expressed in %). Paired two-tailed Student’s t test was used to determine the significance of the results, the level of significance being set at 5%.

This test was applied to raw-data values, as well as to the evolution in the various parameters over the entire duration of the study (compared to T0).


4. ETHICAL AND LEGAL CONSIDERATIONS

4.1. Study personnel The investigator asserts that the study manager and all the persons who have participated in this study had the required qualifications and abilities to carry it out.

4.2. Archiving of the data Dual archiving is ensured by using both paper and IT storage media: paper files are kept in a locked archiving room. The investigator will keep a copy of the protocol signed by both himself and by the Study Sponsor, as well as the original “observation records” (and all associated documents), the participation consents, and all project-related documents of any type for a 10-year period following delivery of the final reports. All these documents will be accessible upon request for inspection by the study sponsor or their representative. The investigator will inform the study sponsor of his intention to proceed with their destruction after the 10-year period.

4.3. Anonymity of the subjects The subjects were identified for the study sponsor using a five-character alphanumeric code.

4.4. Consent to participate in the study An information form was given to each subject providing full details about the study and: Its objectives, methods, and duration; Expected benefits, constraints, and potential risks (particularly should the study have been

discontinued); The testing and evaluation period, the amount of the compensation, the right of access to

data files and their later destruction. This information enabled the subjects to sign their participation consent form freely and unequivocally, in the knowledge that they were fully aware of testing details.


4.5. Confidentiality All the information, data, and results of the study are confidential. All persons having access to such data were informed about their confidentiality. Medical information obtained by the investigator during the recruitment and admission procedures were handled confidentially. Nominal information of this type should not be transmitted to the study sponsor. But in cases of adverse event reactions, data should have been given to the study sponsor. The investigator and individuals conducting the testing, are bound by professional secrecy concerning the nature of the products under study, the trials, the subjects, and the final results.

4.6. Quality Assurance The entire file (protocol, study-related documents, results, report) was subject to quality assurance procedures. The protocol was audited. Specific procedures and data from this study were controlled. Other relevant procedures and data are also checked periodically. The final report was reviewed to ensure that it accurately describes the methods and procedures, and that the results accurately reflect the raw data. Reports on these activities were made to the Study Director and to the Management. The following audits were performed: Audit of the Study Description Form: June 05, 2007; Audit of the Study Protocol: May 30, 2007; Audit of the Subjects’s recruitment: June 06, 2007; Audit of the CRFs: June 06, July 17 and August 07, 2007; Audit of the Raw Data and Results: July 18 and August 07, 2007; Audit of the Study Report: October 16, 2007.

4.7. Regulations This study, which had no direct therapeutic purpose, was undertaken according to the most recent recommendations given by the World Medical Association (Helsinki Statement 1964, amended in Edinburgh, Scotland, 2000).

4.8. Practical considerations A preliminary agreement between the Investigator and the study sponsor, concerned by the present contract, is necessary for any publication or communication directly concerning the two parties. They must both take the initiative to inform each other if a change is to occur.


5. RESULTS

5.1. Protocol adherence One subject (F1557) has presented a very important darkening of the skin during the test (more than 5.0° decrease in ITA°). Since exposing herself intentionally to the sun or to UV was proscribed during the entire duration of the study (cf § 3.1.3.), this subject has been excluded from the expression of the results. No other deviation from the protocol has been observed during the study time course.

5.2. Description of the study population Twenty-two (22) subjects were enrolled in the study. One subject (F2798) was absent at T+1 month and at T+2 months for personal reasons. This absence was unrelated to the tested products. The main characteristics of the population at T0 are summarized in the Table 1 presented below (and in Appendix 1).

Table 1: Description of the main characteristics of the panel at T0 (S.D.: standard deviation)

Number of subjects 22 Mean age (S.D.) in years 31.6 (7.0)

Min age (years) 18 Max age (years) 46

Twenty-two (22) subjects were enrolled in the study. Then:

- Subject F2798 was absent at T+1 month and at T+2 months; - Subject F1557 was excluded from the study (see § 5.1.).

Therefore 20 subjects completed the study (cf Table 2 thereafter) and the population at the different time points was:


Table 2: Number of subjects present and assessable at the different examination times

T0 21 T+1 month 20 T+2 months 20

5.3. Compliance of the subjects All the data relative to the monitoring of the use of the tested products by the subjects are presented in Appendix 2. The Table 3 presented below summarizes the mean consumptions of the tested products by the panel.

Table 3: Summary of the consumption of the tested products

Consumption of the active test product W1

Mean values expressed in grams (± standard deviation) Minimum Maximum

After 1 month 23.14 g (± 15.14) 7.72 g 75.91 g After 2 months 40.57 g (± 17.34) 15.12 g 81.71 g

Consumption of the placebo W4 Mean values expressed in grams

(± standard deviation) Minimum Maximum

After 1 month 24.29 g (± 14.47) 7.67 g 68.84 g After 2 months 42.88 g (± 16.83) 17.99 g 75.79 g

Table 3 above shows that the consumptions of both test products were extremely similar during the study period (no statistical differences were found between the utilizations of the two tested products after 1 month or after 2 months). Therefore it is possible to compare the results obtained with the test product W1 with those obtained with the placebo W4. Nevertheless the range of product’s use was very large for each tested product: from 15.12 grams (subject F2390) to 81.71 grams (subject F1091) after 2 months of test in the case of the product W1, from 17.99 grams (subject F2390) to 75.79 grams (subject F1091) after 2 months of test in the case of the product W4. This large range of consumption is very commonly observed for this kind of cosmetic product. The quantities of test products W1 and W4 used during this 2 month- study were satisfactory. Therefore we can conclude that the compliance of the subjects regarding to the utilization of the test products was very satisfactory.


5.4. Cutaneous acceptability, tolerance No subject has spontaneously reported the occurrence of adverse, unwanted or unexpected events during the study. Therefore we can conclude that the two tested products W1 and W4, applied twice daily during 2 months, were perfectly well tolerated by the subjects.

5.5. Chromametry results Results of the chromametry measurements are presented in Appendix 3 (T+1 month) and in Appendix 4 (T+2 months). Results of the color analysis, at baseline and after 1 month and 2 months of treatment with the two tested products, are summarized in the Table 4 presented below. In this table, only the results relative to the determination of L* and ITA° are shown since these parameters were considered for the assessment of the whitening-lightening effect of the tested products (for the other parameters, see Appendices 3 and 4).

Table 4: Mean variations of the chromametry parameters for the skin treated with the product W1 or with the product W4 during 2 months. Mean values at T0 and T+n month(s) for the different

investigated parameters and their corresponding variations expressed as % compared to baseline.

Treated with W1 Treated with W4 L* 57.11 57.26

T0 ITA° 20.47 21.07 L* 57.75 57.19

T+1 month ITA° 22.05 20.77 L* +1.1% (p<0.01) -0.1% (ns) Variation between T0

and T+1 month ITA° +7.7% (p<0.01) -1.4% (ns) L* 58.10 57.49

T+2 months ITA° 23.28 21.81 L* +1.7% (p<1.10-3) +0.4% (ns) Variation between T0

and T+2 months ITA° +13.7% (p<1.10-3) +3.5% (p<0.05) ns: not significant

5.5.1. After 1 month After 1 month of test, significant increases have been observed in the Luminance L* (+1.1% compared to baseline; p<0.01) and in the individual Typological Angle ITA° (+7.7%; p<0.01)


indicated that a significant lightening of the skin treated with the test product W1 took place between T0 and T+1 month. During the same period, no significant variations were also observed for the Luminance L* or for the Individual Typological Angle ITA° for the skin treated with the product W4. It should be noted that the variations in L* and in ITA° corresponded to a slight and non significant darkening of the skin. When the variations observed for the skin treated with the test product W1 were compared with the variations observed for the skin treated with the product W4, significant differences were observed for the Luminance L* (+1.1% versus -0.1% respectively; p<1.10-3) and for the Individual Typological Angle ITA° (+7.7% versus -1.4% respectively; p<1.10-3). These data indicated that the lightening observed for the skin treated with the test product W1 was significantly superior to the effect observed for the skin treated with the placebo W4, after 1 month of utilization of the products.

5.5.2. After 2 months After 2 months of test, significant increases have been observed in the Luminance L* (+1.7% compared to baseline; p<0.01) and in the individual Typological Angle ITA° (+13.7%; p<0.01) indicated that a significant lightening of the skin treated with the test product W1 took place between T0 and T+2 months. During the same period, a significant increase in the Individual Typological Angle ITA° was also observed for the skin treated with the placebo W4 (+3.5%; p<0.05), although less important than the increase observed in the case of the skin treated with W1. A slight and non significant increase in the Luminance L* was also noted (+0.4%). These data demonstrated that both products W1 and W4 were able to significantly whiten the skin after 2 months of treatment. When the variations observed for the skin treated with the test product W1 were compared with the variations observed for the skin treated with the product W4, significant differences were observed for the Luminance L* (+1.7% versus +0.4% respectively; p<0.01) and for the Individual Typological Angle ITA˚ (+13.7% versus +3.5% respectively; p<0.01). These data indicated that the lightening observed for the skin treated with the test product W1 was significantly superior to the effect observed for the skin treated with the placebo W4, after 2 months of utilization of the products. Figures 2 and 3 thereafter illustrate the effects induced by the two tested products upon the color of the skin.

Evolution of the LuminanceW1W4

1.7

0.4

-0.20.00.20.40.60.81.01.21.41.61.8

Vari

atio

ns (%

/T0)

1.1

-0.1

After 1 month After 2 months

Figure 2: Evolution of the mean variation in the luminance L* (expressed in % compared to baseline)

for the skin treated with the test product W1 and for the skin treated with the placebo W4


7.7

-1.4

13.7

3.5

-2

0

2

4

Vari

a

6

8

10

12

14

tions

(%/T

0)

After 1 month After 2 months

Evolution of the Individual Typological AngleW1W4

Figure 3: Evolution of the mean variation in the Individual Typological Angle ITA˚ (expressed

in % compared to baseline) for the skin treated with the test product W1 and for the skin treated with the placebo W4

APPENDIX 1

STUDY POPULATION

Codes Age (years)

F0528 38

F0854 31

F1091 24

F1109 39

F1262 36

F1294 37

F1295 26

F1322 28

F1323 40

F1496 29

F1557 29

F1818 36

F1895 36

F2385 26

F2390 46

F2598 24

F2629 18

F2649 42

F2668 25

F2793 29

F2795 30

F2798 27

S.D. 7.0

Max. 46

Min. 18

Subjects 22

S.D.= Standard Deviation

REFERENCES OF THE TEST PRODUCTS: Product W1 versus Product W4STUDY REF.: C03-PF02-LP-MI07

Mean 31.6

Population

APPENDIX 2

MONITORING OF THE TEST PRODUCTS’ UTILIZATION

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

PRO

DU

CT'

S W

EIG

HT

ANA

LYSI

SW

eigh

ing

of p

rodu

cts

at T

+1 m

onth

Cod

esT0

T+1

mon

thC

onsu

mpt

ion

afte

r 1 m

onth

Cod

esT0

T+1

mon

thC

onsu

mpt

ion

afte

r 1 m

onth

F052

813

7.14

100.

4636

.68

F052

813

5.87

101.

6634

.21

F085

413

6.08

111.

0125

.07

F085

413

4.00

110.

0423

.95

F109

114

1.46

65.5

575

.91

F109

113

5.84

67.0

068

.84

F110

913

4.55

116.

4218

.13

F110

913

5.35

121.

8113

.55

F126

213

4.78

105.

3129

.48

F126

213

3.12

96.4

236

.70

F129

413

7.81

123.

6514

.17

F129

413

8.87

119.

9818

.89

F129

513

5.35

115.

1320

.22

F129

513

0.19

114.

6915

.50

F132

212

8.35

107.

7020

.65

F132

212

9.52

110.

4719

.05

F132

312

7.07

108.

8718

.20

F132

314

0.62

119.

0121

.61

F149

612

3.95

111.

9711

.98

F149

613

2.32

119.

1713

.15

F155

7N

EN

EN

EF1

557

NE

NE

NE

F181

813

2.35

115.

1117

.24

F181

813

6.38

116.

7019

.68

F189

513

5.14

117.

0618

.08

F189

513

8.47

116.

4422

.03

F238

513

6.68

102.

8233

.86

F238

513

6.36

105.

8030

.56

F239

013

8.21

128.

849.

37F2

390

140.

2612

8.54

11.7

2F2

598

140.

2511

6.55

23.7

0F2

598

142.

5211

2.99

29.5

2F2

629

138.

4013

0.67

7.72

F262

912

7.37

119.

707.

67F2

649

132.

2110

1.32

30.8

8F2

649

132.

3593

.95

38.4

0F2

668

132.

4412

2.09

10.3

5F2

668

139.

7113

0.25

9.46

F279

313

6.75

126.

999.

76F2

793

129.

5911

8.26

11.3

3F2

795

128.

2296

.86

31.3

6F2

795

134.

9194

.94

39.9

7F2

798

138.

45A

bs.

Abs.

F2

798

137.

61Ab

s.

Abs.

S.D

.4.

5614

.44

15.1

4S.

D.

4.09

14.5

614

.47

Med

ian

135.

3511

3.54

19.2

1M

edia

n13

5.84

115.

5720

.65

Min

imum

123.

9565

.55

7.72

Min

imum

127.

3767

.00

7.67

Max

imum

141.

4613

0.67

75.9

1M

axim

um14

2.52

130.

2568

.84

Subj

ects

2120

20Su

bjec

ts21

2020

S.D

.: St

anda

rd D

evia

tion

Abs.

: Abs

ent

NE:

Not

exp

loite

dS.

D.:

Stan

dard

Dev

iatio

nAb

s.: A

bsen

tN

E: N

ot e

xplo

ited

PR

OD

UC

T: W

1 P

RO

DU

CT:

W4

Mea

n13

4.55

111.

2223

.14

Mea

n13

5.30

110.

8924

.29

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

PRO

DU

CT'

S W

EIG

HT

ANAL

YSIS

Wei

ghin

g of

pro

duct

s at

T+2

mon

ths

Cod

esT0

T+2

mon

ths

Con

sum

ptio

n af

ter 2

mon

ths

Cod

esT0

T+2

mon

ths

Con

sum

ptio

n af

ter 2

mon

ths

F052

813

7.14

76.2

160

.93

F052

813

5.87

73.4

662

.41

F085

413

6.08

80.8

155

.27

F085

413

4.00

79.7

154

.29

F109

114

1.46

59.7

581

.71

F109

113

5.84

60.0

575

.79

F110

913

4.55

104.

2630

.29

F110

913

5.35

104.

1431

.21

F126

213

4.78

79.7

655

.02

F126

213

3.12

79.8

753

.25

F129

413

7.81

103.

6834

.13

F129

413

8.87

97.1

241

.75

F129

513

5.35

90.4

044

.95

F129

513

0.19

92.1

238

.06

F132

212

8.35

89.2

139

.13

F132

212

9.52

89.3

940

.13

F132

312

7.07

91.3

735

.70

F132

314

0.62

91.8

348

.79

F149

612

3.95

103.

9619

.99

F149

613

2.32

110.

3621

.96

F155

7N

EN

EN

EF1

557

NE

NE

NE

F181

813

2.35

99.8

732

.48

F181

813

6.38

97.2

239

.17

F189

513

5.14

96.1

239

.01

F189

513

8.47

91.9

346

.55

F238

513

6.68

87.9

448

.73

F238

513

6.36

91.8

344

.53

F239

013

8.21

123.

0915

.12

F239

014

0.26

122.

2717

.99

F259

814

0.25

97.1

943

.06

F259

814

2.52

94.0

048

.51

F262

913

8.40

116.

0522

.35

F262

912

7.37

105.

2522

.12

F264

913

2.21

76.6

155

.59

F264

913

2.35

70.3

362

.03

F266

813

2.44

112.

8119

.63

F266

813

9.71

120.

2419

.47

F279

313

6.75

117.

2819

.47

F279

312

9.59

107.

2422

.35

F279

512

8.22

69.3

658

.86

F279

513

4.91

67.7

267

.19

F279

813

8.45

Abs

. A

bs.

F279

813

7.61

Abs

. A

bs.

S.D

.4.

5616

.90

17.3

4S.

D.

4.09

16.8

516

.83

Med

ian

135.

3593

.75

39.0

7M

edia

n13

5.84

92.0

243

.14

Min

imum

123.

9559

.75

15.1

2M

inim

um12

7.37

60.0

517

.99

Max

imum

141.

4612

3.09

81.7

1M

axim

um14

2.52

122.

2775

.79

Sub

ject

s21

2020

Sub

ject

s21

2020

S.D

.: St

anda

rd D

evia

tion

Abs.

: Abs

ent

NE

: Not

exp

loite

dS.

D.:

Stan

dard

Dev

iatio

nAb

s.: A

bsen

tN

E: N

ot e

xplo

ited

PR

OD

UC

T: W

1 P

RO

DU

CT:

W4

Mea

n13

4.55

93.7

940

.57

Mea

n13

5.30

92.3

042

.88

APPENDIX 3

CHROMAMETRY RESULTS AT T+1 MONTH

STUDY REF.: C03-PF02-LP-MI07

CHROMAMETRIC ANALYSIS EVALUATION OF THE EFFICACY OF WHITENING PRODUCTS

REFERENCES OF THE TEST PRODUCTS: Product W1 versus Product W4

Mean SD Mean SD

L 57.11 2.89 57.26 2.57

a* 12.55 1.20 12.58 1.15

b* 18.79 1.32 18.71 1.36

C* 22.64 1.05 22.59 0.97

ITA° 20.47 8.19 21.07 7.32

L 57.75 2.86 57.19 2.59

a* 11.89 1.41 12.24 1.21

b* 18.91 1.42 18.86 1.46

C* 22.40 1.03 22.54 1.06

ITA° 22.05 7.82 20.77 7.45

L

a*

b*

C*

ITA°

SD= Standard Deviation

Dates of measurements

30/05/07, 01/06/07

28-29/06/07

W1

7.7%

W4W1Variations (%)

T0

T+1 m.

(T+1 m. - T0)/T0

-1.1% -0.2%

-1.4%

0.6% 0.8%

1.1%

-5.2%

-0.1%

-2.7%

Mean of the raw values

T0

W4

T+1 month

STUDY REF.: C03-PF02-LP-MI07 CHROMAMETRIC ANALYSIS

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

EVALUATION OF THE EFFICACY OF WHITENING PRODUCTSREFERENCES OF THE TEST PRODUCTS: Product W1 versus Product W4

STATISTICS

Threshold value

Each subject was her own reference

Observation

Comparison of raw values between T0 and T+1 month

L

Comparison a*

T+1 m. versus T0 b*

C*

ITA°

Threshold value


Observation

Comparison of variations between T0 and T+1 month

L

Comparison a*

W1 versus W4 b*

C*

ITA° 2.41E-04

9.76E-01 No

4.50E-02

1.26E-04

4.01E-02

0.05

Paired groups

Two-tailed

Treated - Group 1Variations between T0 and T+1 m.

p(T<=t) Significant 5% ?

Student's t test Choice

3.14E-02

No

Choice

0.05

Paired groups

W4

p(T<=t) Significant 5% ? p(T<=t) Significant 5% ?

W1Treated - Group 1

Student's t test

Two-tailed

1.50E-03

5.26E-03

3.44E-01

3.35E-01

6.03E-01

4.26E-02

2.64E-01

No

No

No

No7.37E-011.27E-03

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

CH

RO

MAM

ETR

IC A

NAL

YSIS

ON

OF

THE

EFFI

CAC

Y O

F W

HIT

ENIN

G

Mea

n57

.11

57.7

512

.55

11.8

918

.79

18.9

122

.64

22.4

020

.47

22.0

5M

ean

57.2

657

.19

12.5

812

.24

18.7

118

.86

22.5

922

.54

21.0

720

.77

SDSD

EVAL

UAT

I P

RO

DU

CTS

REF

EREN

CES

OF

THE

TEST

PR

OD

UC

TS:P

rodu

ct W

1 ve

rsus

Pro

duct

W4

Cod

esT0

T +1

m .

T0T

+1m

.T0

T +1

m .

T0T

+1m

.T0

T +1

m .

Cod

esT0

T +1

m .

T0T

+1m

.T0

T +1

m .

T0T

+1m

.T0

T +1

m .

F052

859

.87

59.4

711

.71

11.4

218

.33

17.6

521

.75

21.0

228

.30

28.2

2F0

528

59.9

858

.65

11.8

211

.66

18.2

117

.96

21.7

121

.41

28.7

225

.72

F085

458

.37

59.3

112

.52

11.2

320

.57

20.6

224

.08

23.4

822

.14

24.3

0F0

854

58.8

558

.49

11.9

711

.40

20.3

220

.81

23.5

823

.73

23.5

322

.19

F109

158

.84

57.6

712

.79

14.4

116

.81

16.9

221

.12

22.2

227

.74

24.3

9F1

091

59.0

057

.44

12.5

614

.32

16.7

116

.61

20.9

021

.93

28.3

124

.13

F110

958

.81

58.3

612

.25

12.6

417

.41

16.2

021

.29

20.5

526

.84

27.3

0F1

109

58.4

158

.50

13.0

312

.54

16.9

716

.73

21.4

020

.91

26.3

626

.93

F126

254

.69

55.9

314

.24

12.5

218

.63

19.1

523

.45

22.8

814

.13

17.2

1F1

262

55.3

756

.01

13.7

712

.71

19.1

919

.27

23.6

223

.08

15.6

317

.32

F129

456

.63

57.1

712

.61

12.2

720

.74

20.5

724

.27

23.9

517

.73

19.2

2F1

294

55.5

955

.96

12.7

312

.39

19.7

119

.63

23.4

623

.21

15.8

316

.89

F129

550

.31

50.4

913

.19

11.7

318

.96

19.4

523

.10

22.7

10.

941.

44F1

295

50.8

650

.65

12.4

411

.91

19.4

219

.92

23.0

623

.21

2.54

1.87

F132

255

.48

56.4

212

.50

11.8

219

.60

19.5

823

.25

22.8

715

.62

18.1

5F1

322

54.5

054

.37

12.5

612

.23

19.1

919

.66

22.9

323

.15

13.2

012

.53

F132

356

.84

56.6

613

.26

13.2

718

.72

18.4

722

.94

22.7

420

.07

19.8

3F1

323

56.6

056

.22

12.2

212

.86

19.3

918

.71

22.9

222

.70

18.8

018

.39

F149

658

.73

59.7

312

.45

10.0

818

.06

19.1

821

.94

21.6

725

.80

26.9

0F1

496

58.7

258

.66

11.3

210

.63

18.8

719

.29

22.0

022

.03

24.8

024

.18

F155

7N

EN

EN

EN

EN

EN

EN

EN

EN

EN

EF1

557

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

F181

859

.45

61.1

712

.71

11.2

217

.19

18.1

921

.38

21.3

728

.80

31.5

5F1

818

58.5

359

.34

14.1

712

.13

17.0

018

.11

22.1

321

.80

26.6

527

.28

F189

552

.74

53.8

415

.60

14.4

017

.08

17.9

723

.13

23.0

39.

1112

.06

F189

554

.73

53.9

914

.43

13.8

818

.15

18.5

923

.19

23.2

014

.61

12.1

1F2

385

58.7

159

.33

11.6

710

.61

18.7

319

.48

22.0

722

.18

24.9

425

.59

F238

558

.11

58.5

611

.87

11.3

918

.53

18.7

722

.01

21.9

623

.64

24.5

2F2

390

58.3

358

.25

10.9

710

.77

20.6

720

.77

23.4

023

.40

21.9

521

.66

F239

058

.37

57.2

110

.73

11.6

321

.00

20.8

123

.58

23.8

421

.73

19.1

1F2

598

54.7

956

.93

14.3

611

.94

18.4

218

.42

23.3

621

.95

14.5

820

.62

F259

855

.71

56.2

713

.74

12.4

018

.46

18.2

623

.01

22.0

717

.19

18.9

5F2

629

56.0

158

.92

11.8

210

.72

19.7

520

.06

23.0

222

.74

16.9

323

.97

F262

956

.47

59.0

212

.46

11.0

119

.52

20.4

723

.16

23.2

418

.34

23.7

8F2

649

58.3

459

.53

12.9

212

.49

18.3

117

.63

22.4

121

.61

24.4

928

.39

F264

957

.78

59.5

414

.06

13.4

718

.12

17.6

822

.94

22.2

323

.24

28.3

5F2

668

62.5

963

.70

11.0

39.

7517

.85

18.0

420

.98

20.5

135

.20

37.2

1F2

668

62.4

662

.74

11.7

610

.62

17.6

016

.88

21.1

719

.94

35.3

037

.04

F279

356

.87

58.4

511

.31

10.2

021

.73

21.8

124

.50

24.0

817

.54

21.1

8F2

793

56.7

257

.79

11.3

610

.74

21.6

621

.74

24.4

624

.25

17.2

419

.71

F279

552

.81

53.7

512

.88

14.3

018

.03

17.9

622

.16

22.9

68.

8611

.79

F279

554

.72

54.4

214

.36

14.9

716

.51

17.2

321

.88

22.8

215

.95

14.3

9F2

798

60.1

8A

bs.

10.6

7A

bs.

19.0

4A

bs.

21.8

3Ab

s.28

.13

Abs

.F2

798

60.9

3Ab

s.10

.80

Abs

.18

.33

Abs

.21

.28

Abs

.30

.81

Abs

.

2.89

2.86

1.20

1.41

1.32

1.42

1.05

1.03

8.19

7.82

2.57

2.59

1.15

1.21

1.36

1.46

0.97

1.06

7.32

7.45

Sub

ject

s21

20S

ubje

cts

2120

SD

= S

tand

ard

Dev

iatio

nA

bs: A

bsen

tN

E: N

ot e

xplo

ited

SD

= S

tand

ard

Dev

iatio

nA

bs: A

bsen

tN

E: N

ot e

xplo

ited

ITA°

Sum

mar

y of

the

raw

val

ues

on th

e gl

obal

pan

el

b*C

*IT

A°

W1

La*

b*C

*a*

L

W4

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

CH

RO

MAM

ETR

IC A

NAL

YSIS

N O

F TH

E EF

FIC

ACY

OF

WH

ITEN

ING

P

Mea

n0.

79-0

.75

0.13

-0.2

81.

96M

ean

0.12

-0.4

20.

13-0

.12

0.19

SDSD

EVAL

UAT

IOR

OD

UC

TS

REF

EREN

CES

OF

THE

TEST

PR

OD

UC

TS: P

rodu

ct W

1 ve

rsus

Pro

duct

W4

Varia

tions

bet

wee

n T0

and

T+1

mon

th

Cod

esL

a*b*

C*

ITA°

Cod

esL

a*b*

C*

ITA°

F052

8-0

.40

-0.2

9-0

.68

-0.7

3-0

.09

F052

8-1

.33

-0.1

6-0

.25

-0.3

0-3

.01

F085

40.

94-1

.29

0.05

-0.6

02.

16F0

854

-0.3

6-0

.57

0.49

0.14

-1.3

4F1

091

-1.1

71.

620.

111.

10-3

.35

F109

1-1

.56

1.76

-0.1

01.

03-4

.18

F110

9-0

.45

0.39

-1.2

1-0

.74

0.46

F110

90.

09-0

.49

-0.2

4-0

.49

0.57

F126

21.

24-1

.72

0.52

-0.5

73.

08F1

262

0.64

-1.0

60.

08-0

.54

1.69

F129

40.

54-0

.34

-0.1

7-0

.32

1.49

F129

40.

37-0

.34

-0.0

8-0

.25

1.06

F129

50.

18-1

.46

0.49

-0.3

80.

51F1

295

-0.2

1-0

.53

0.50

0.15

-0.6

7F1

322

0.94

-0.6

8-0

.02

-0.3

82.

53F1

322

-0.1

3-0

.33

0.47

0.22

-0.6

7F1

323

-0.1

80.

01-0

.25

-0.2

0-0

.24

F132

3-0

.38

0.64

-0.6

8-0

.22

-0.4

1F1

496

1.00

-2.3

71.

12-0

.27

1.10

F149

6-0

.06

-0.6

90.

420.

02-0

.63

F155

7N

EN

EN

EN

EN

EF1

557

NE

NE

NE

NE

NE

F181

81.

72-1

.49

1.00

-0.0

12.

75F1

818

0.81

-2.0

41.

11-0

.33

0.64

F189

51.

10-1

.20

0.89

-0.1

02.

95F1

895

-0.7

4-0

.55

0.44

0.01

-2.4

9F2

385

0.62

-1.0

60.

750.

110.

65F2

385

0.45

-0.4

80.

24-0

.05

0.88

F239

0-0

.08

-0.2

00.

100.

00-0

.29

F239

0-1

.16

0.90

-0.1

90.

26-2

.62

F259

82.

14-2

.42

0.00

-1.4

06.

04F2

598

0.56

-1.3

4-0

.20

-0.9

41.

76F2

629

2.91

-1.1

00.

31-0

.27

7.05

F262

92.

55-1

.45

0.95

0.09

5.44

F264

91.

19-0

.43

-0.6

8-0

.80

3.90

F264

91.

76-0

.59

-0.4

4-0

.71

5.11

F266

81.

11-1

.28

0.19

-0.4

82.

02F2

668

0.28

-1.1

4-0

.72

-1.2

21.

75F2

793

1.58

-1.1

10.

08-0

.42

3.63

F279

31.

07-0

.62

0.08

-0.2

12.

48F2

795

0.94

1.42

-0.0

70.

802.

94F2

795

-0.3

00.

610.

720.

94-1

.57

F279

8Ab

s.Ab

s.Ab

s.Ab

s.Ab

s.F2

798

Abs

.Ab

s.A

bs.

Abs

.Ab

s.

0.96

1.06

0.58

0.54

2.32

0.99

0.87

0.51

0.54

2.49

Subj

ects

20Su

bjec

ts20

SD

= S

tand

ard

Dev

iatio

nA

bs: A

bsen

tSD

= St

anda

rd D

evia

tion

Abs:

Abs

ent

NE:

Not

exp

loite

dN

E: N

ot e

xplo

ited

(T+1

m.)

- T0

W4

(T+1

m.)

- T0

W1

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

EVAL

UAT

IO P

RO

DU

CTS

REF

EREN

CES

OF

THE

TEST

PR

OD

UC

TS: P

rodu

ct W

1 ve

rsus

Pro

duct

W4

Varia

tions

bet

wee

n W

1 an

d W

4D

iffer

ence

s be

twee

n pr

oduc

ts W

1 an

d W

4

Cod

esL

a*b*

C*

ITA

°F0

528

0.93

-0.1

3-0

.43

-0.4

32.

92F0

854

1.30

-0.7

2-0

.44

-0.7

53.

50F1

091

0.39

-0.1

40.

210.

080.

82F1

109

-0.5

40.

88-0

.97

-0.2

5-0

.12

F126

20.

60-0

.66

0.44

-0.0

31.

39F1

294

0.17

0.00

-0.0

9-0

.07

0.43

F129

50.

39-0

.93

-0.0

1-0

.53

1.17

F132

21.

07-0

.35

-0.4

9-0

.59

3.20

F132

30.

20-0

.63

0.43

0.02

0.17

F149

61.

06-1

.68

0.70

-0.2

91.

73F1

557

NE

NE

NE

NE

NE

F181

80.

910.

55-0

.11

0.33

2.12

F189

51.

84-0

.65

0.45

-0.1

25.

44F2

385

0.17

-0.5

80.

510.

16-0

.23

F239

01.

08-1

.10

0.29

-0.2

62.

34F2

598

1.58

-1.0

80.

20-0

.46

4.28

F262

90.

360.

35-0

.64

-0.3

61.

61F2

649

-0.5

70.

16-0

.24

-0.1

0-1

.21

F266

80.

83-0

.14

0.91

0.75

0.27

F279

30.

51-0

.49

0.00

-0.2

11.

16F2

795

1.24

0.81

-0.7

9-0

.14

4.50

F279

8Ab

s.Ab

s.Ab

s.Ab

s.Ab

s.

0.63

0.66

0.51

0.34

1.76

Subj

ects

20

SD

= St

anda

rd D

evia

tion

Abs

: Abs

ent

NE:

Not

exp

loite

d

W1

-W4

(T+1

m.)

- T0

CH

RO

MAM

ETR

IC A

NAL

YSIS

N O

F TH

E EF

FIC

ACY

OF

WH

ITEN

ING

Mea

n0.

68-0

.33

0.00

-0.1

61.

77

SD

APPENDIX 4

CHROMAMETRY RESULTS AT T+2 MONTHS



Mean SD Mean SD

L 57.11 2.89 57.26 2.57

a* 12.55 1.20 12.58 1.15

b* 18.79 1.32 18.71 1.36

C* 22.64 1.05 22.59 0.97

ITA° 20.47 8.19 21.07 7.32

L 58.10 2.66 57.49 2.44

a* 12.16 1.19 12.41 0.99

b* 18.72 1.45 18.71 1.59

C* 22.36 1.23 22.49 1.20

ITA° 23.28 7.55 21.81 7.32

La*b*C*

ITA°

S.D.: Standard Deviation

Mean of the raw values

T0

W4

T+2 months

(T+2 m. - T0)/T0 -1.2% -0.4%

3.5%

-0.4% 0.0%

1.7%-3.1%

0.4%-1.3%

W1Variations (%)

T0

T+2 m.

13.7%

W4

Dates of measurements

30/05/07, 01/06/07

26-27/07/07

W1


Yes

Yes

Yes

YesYes


STATISTICS

Threshold value


Observation

Comparison of raw values between T0 and T+2 months

LComparison a*

T+2 m. versus T0 b*C*

ITA°

Threshold value


Observation

Comparison of variations between T0 and T+2 months

LComparison a*

W1 versus W4 b*C*

ITA° 4.16E-03

7.88E-01 No

1.93E-01 No

3.58E-03

3.33E-01 No

0.05

Paired groups

Two-tailed

Treated - Group 1Variations between T0 and T+2 m.

p(T<=t) Significant 5% ?

Student's t test Choice

6.67E-02

No

No

No

Choice

0.05

Paired groups

W4

p(T<=t) Significant 5% ? p(T<=t) Significant 5% ?

W1Treated - Group 1

Student's t test

Two-tailed

2.79E-04

6.52E-02

7.16E-01

2.62E-01

5.20E-02

2.07E-01

9.05E-01

No

No

No

No

4.01E-021.34E-04

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

CH

RO

MA

MET

RIC

AN

ALY

SIS

ON

OF

THE

EFFI

CAC

Y O

F W

HIT

ENIN

G

Mea

n57

.11

58.1

012

.55

12.1

618

.79

18.7

222

.64

22.3

620

.47

23.2

8M

ean

57.2

657

.49

12.5

812

.41

18.7

118

.71

22.5

922

.49

21.0

721

.81

S.D

.S.

D.

EVAL

UAT

I P

RO

DU

CTS

REF

EREN

CES

OF

THE

TEST

PR

OD

UC

TS:P

rodu

ct W

1 ve

rsus

Pro

duct

W4

Cod

esT0

T +2

m .

T0T

+2 m

.T0

T +2

m .

T0T

+2 m

.T0

T +2

m .

Cod

esT0

T +2

m .

T0T

+2 m

.T0

T +2

m .

T0T

+2 m

.T0

T +2

m .

F052

859

.87

60.3

711

.71

11.9

718

.33

17.5

321

.75

21.2

328

.30

30.6

1F0

528

59.9

859

.35

11.8

211

.85

18.2

117

.78

21.7

121

.37

28.7

227

.74

F085

458

.37

59.0

012

.52

12.2

820

.57

20.4

124

.08

23.8

222

.14

23.8

0F0

854

58.8

558

.49

11.9

710

.99

20.3

220

.98

23.5

823

.68

23.5

322

.03

F109

158

.84

58.5

312

.79

14.1

816

.81

17.4

121

.12

22.4

527

.74

26.1

0F1

091

59.0

058

.74

12.5

612

.45

16.7

117

.62

20.9

021

.57

28.3

126

.38

F110

958

.81

59.0

812

.25

12.0

417

.41

16.1

321

.29

20.1

326

.84

29.3

8F1

109

58.4

157

.76

13.0

312

.78

16.9

715

.60

21.4

020

.17

26.3

626

.45

F126

254

.69

56.7

414

.24

12.1

218

.63

19.4

223

.45

22.8

914

.13

19.1

4F1

262

55.3

755

.75

13.7

712

.05

19.1

920

.19

23.6

223

.51

15.6

315

.90

F129

456

.63

57.1

612

.61

12.6

320

.74

20.2

324

.27

23.8

517

.73

19.4

9F1

294

55.5

955

.50

12.7

312

.78

19.7

120

.33

23.4

624

.01

15.8

315

.14

F129

550

.31

51.1

113

.19

12.0

918

.96

19.9

123

.10

23.2

90.

943.

19F1

295

50.8

651

.68

12.4

413

.74

19.4

219

.36

23.0

623

.74

2.54

4.96

F132

255

.48

58.0

012

.50

11.6

919

.60

19.4

323

.25

22.6

815

.62

22.3

8F1

322

54.5

055

.75

12.5

611

.79

19.1

920

.42

22.9

323

.58

13.2

015

.73

F132

356

.84

56.9

213

.26

12.9

018

.72

18.2

522

.94

22.3

520

.07

20.7

7F1

323

56.6

056

.75

12.2

212

.05

19.3

919

.19

22.9

222

.66

18.8

019

.38

F149

658

.73

59.0

812

.45

11.0

918

.06

18.1

221

.94

21.2

425

.80

26.6

2F1

496

58.7

258

.33

11.3

211

.53

18.8

718

.64

22.0

021

.92

24.8

024

.08

F155

7N

EN

EN

EN

EN

EN

EN

EN

EN

EN

EF1

557

NE

NE

NE

NE

NE

NE

NE

NE

NE

NE

F181

859

.45

62.3

512

.71

10.3

917

.19

17.6

921

.38

20.5

228

.80

34.9

2F1

818

58.5

360

.78

14.1

712

.16

17.0

016

.98

22.1

320

.89

26.6

532

.41

F189

552

.74

55.2

415

.60

14.1

717

.08

18.2

823

.13

23.1

39.

1116

.00

F189

554

.73

54.2

314

.43

13.6

118

.15

18.7

223

.19

23.1

414

.61

12.7

3F2

385

58.7

159

.48

11.6

710

.98

18.7

319

.22

22.0

722

.14

24.9

426

.25

F238

558

.11

58.5

011

.87

11.5

418

.53

18.6

822

.01

21.9

623

.64

24.4

7F2

390

58.3

356

.76

10.9

712

.63

20.6

720

.32

23.4

023

.93

21.9

518

.40

F239

058

.37

58.2

010

.73

12.3

321

.00

20.0

723

.58

23.5

521

.73

22.2

2F2

598

54.7

956

.99

14.3

612

.90

18.4

218

.18

23.3

622

.29

14.5

821

.03

F259

855

.71

56.1

213

.74

14.4

118

.46

17.4

123

.01

22.6

017

.19

19.3

7F2

629

56.0

158

.18

11.8

211

.26

19.7

520

.09

23.0

223

.03

16.9

322

.15

F262

956

.47

58.0

412

.46

11.5

619

.52

19.9

023

.16

23.0

118

.34

22.0

0F2

649

58.3

459

.77

12.9

212

.24

18.3

116

.33

22.4

120

.41

24.4

930

.89

F264

957

.78

60.0

714

.06

13.0

418

.12

16.9

222

.94

21.3

623

.24

30.7

6F2

668

62.5

963

.43

11.0

310

.65

17.8

518

.04

20.9

820

.95

35.2

036

.67

F266

862

.46

62.7

711

.76

11.6

217

.60

17.0

921

.17

20.6

735

.30

36.7

7F2

793

56.8

758

.97

11.3

110

.48

21.7

321

.62

24.5

024

.03

17.5

422

.53

F279

356

.72

56.9

911

.36

11.5

021

.66

21.2

124

.46

24.1

317

.24

18.2

4F2

795

52.8

154

.83

12.8

814

.50

18.0

317

.73

22.1

622

.90

8.86

15.2

4F2

795

54.7

256

.00

14.3

614

.43

16.5

117

.03

21.8

822

.32

15.9

519

.41

F279

860

.18

Abs.

10.6

7Ab

s.19

.04

Abs

.21

.83

Abs.

28.1

3Ab

s.F2

798

60.9

3Ab

s.10

.80

Abs

.18

.33

Abs.

21.2

8A

bs.

30.8

1Ab

s.

2.89

2.66

1.20

1.19

1.32

1.45

1.05

1.23

8.19

7.55

2.57

2.44

1.15

0.99

1.36

1.59

0.97

1.20

7.32

7.32

Sub

ject

s21

20S

ubje

cts

2120

S.D

.: S

tand

ard

Dev

iatio

nA

bs: A

bsen

tN

E: N

ot e

xplo

ited

S.D

.: S

tand

ard

Dev

iatio

nA

bs: A

bsen

tN

E: N

ot e

xplo

ited

a*L

W4

a*b*

C*

ITA°

Sum

mar

y of

the

raw

val

ues

on th

e gl

obal

pan

el

b*C

*IT

A°

W1

L

STU

DY

REF

.: C

03-P

F02-

LP-M

I07

CH

RO

MAM

ETR

IC A

NAL

YSIS

OF

THE

EFFI

CAC

Y O

F W

HIT

ENIN

G

EVAL

UAT

ION

PRO

DU

CTS

REF

EREN

CES

OF

THE

TEST

PR

OD

UC

TS: P

rodu

ct W

1 ve

rsus

Pro

duct

W4

Varia

tions

bet

wee

n T0

and

T+2

mon

ths

Cod

esL

a*b*

C*

ITA°

Cod

esL

a*b*

C*

ITA°

F052

80.

500.

26-0

.80

-0.5

22.

31F0

528

-0.6

30.

03-0

.43

-0.3

4-0

.99

F085

40.

63-0

.24

-0.1

6-0

.26

1.65

F085

4-0

.36

-0.9

80.

660.

10-1

.50

F109

1-0

.31

1.39

0.60

1.33

-1.6

4F1

091

-0.2

6-0

.11

0.91

0.67

-1.9

2F1

109

0.27

-0.2

1-1

.28

-1.1

62.

54F1

109

-0.6

5-0

.25

-1.3

7-1

.23

0.09

F126

22.

05-2

.12

0.79

-0.5

65.

01F1

262

0.38

-1.7

21.

00-0

.11

0.26

F129

40.

530.

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APPENDIX 5

COPY OF THE PROTOCOL

SPINCONTROL ASIA Co., Ltd. 483, 485 Soi Ladprao 101 Ladprao Rd., Wangthonglang, Wangthonglang, Bangkok 10310, THAILAND May 2007

CONFIDENTIAL STUDY PROTOCOL Ref.: C03-PF02-LP-MI07(V01)




Product W1 versus Product W4

Study sponsor:

LIPOTEC C/Isaac Peral 17,

Poligon Industrial Cami Ral, 08850 Gavà, Barcelona, SPAIN

Spincontrol Asia Co., Ltd. 2/44 C03-PF02-LP-MI07-C03-PR(V01)

CONTENT

1. SITE OF EXPERIMENTATION, PARTICIPANTS........................................................4 1.1. SITE OF EXPERIMENTATION ...................................................................................................4 1.2. STUDY SPONSOR....................................................................................................................4 1.3. STUDY MONITOR...................................................................................................................4 1.4. INVESTIGATOR.......................................................................................................................4 1.5. STUDY MANAGER..................................................................................................................4 1.6. TECHNICIANS ........................................................................................................................5 1.7. QUALITY ASSURANCE ...........................................................................................................5

2. SUMMARY OF THE STUDY.............................................................................................6 2.1. OBJECTIVE.............................................................................................................................6 2.2. POPULATION..........................................................................................................................6 2.3. STUDY DESIGN.......................................................................................................................6 2.4. STUDY SCHEDULE AND DURATION.........................................................................................6

3. MATERIALS AND METHODS..........................................................................................8 3.1. SELECTION OF THE SUBJECTS.................................................................................................8

3.1.1. Inclusion criteria ...........................................................................................................8 3.1.2. Exclusion criteria ..........................................................................................................9 3.1.3. Proscriptions and restrictions.......................................................................................9

3.2. DESCRIPTION OF THE PRODUCTS............................................................................................9 3.3. MODALITIES OF UTILIZATION OF THE PRODUCTS, RANDOMIZATION ....................................10 3.4. CUTANEOUS ACCEPTABILITY, ADVERSE EVENTS .................................................................10 3.5. WITHDRAWAL FROM THE STUDY .........................................................................................11 3.6. DISCONTINUANCE OF THE STUDY ........................................................................................11 3.7. TECHNICAL EQUIPMENT.......................................................................................................11 3.8. STUDY DESIGN.....................................................................................................................11 3.9. CHROMAMETRY MEASUREMENTS........................................................................................12

3.9.1. Principle ......................................................................................................................12 3.9.2. Measurements..............................................................................................................13 3.9.3. Evaluation parameters ................................................................................................13 3.9.4. Interpretation of the chromametry parameters...........................................................13

3.10. EXAMINATION SCHEDULE..................................................................................................14 3.11. DATA ANALYSIS AND STATISTICS ......................................................................................14

4. ETHICAL AND LEGAL CONSIDERATIONS ..............................................................15 4.1. STUDY PERSONNEL ..............................................................................................................15 4.2. ARCHIVING OF THE DATA ....................................................................................................15 4.3. AMENDMENTS TO THE PROTOCOL........................................................................................15 4.4. ANONYMITY OF THE SUBJECTS ............................................................................................15 4.5. CONSENT TO PARTICIPATE IN THE STUDY ............................................................................15 4.6. CONFIDENTIALITY ...............................................................................................................16


4.7. STUDY INCIDENTS................................................................................................................16 4.8. QUALITY ASSURANCE .........................................................................................................16 4.9. REGULATIONS .....................................................................................................................17 4.10. PRACTICAL CONSIDERATIONS............................................................................................17 APPENDICES:

Appendix 1: Randomization sheet……………………...……………………............…...….…. 18 Appendix 2: Observations record ……………………...……………………............…...….…. 20 Appendix 3: Subject declaration form (English and Thai versions).............. ......……..….…… 30 Appendix 4: Consent to participate (English and Thai versions) ..………...………….……….. 33 Appendix 5: Subject information form (English and Thai versions)............. ... ..……..….…… 38 Appendix 6: Resume of the Investigator..................................…………… ... ……..…….…… 43


1. SITE OF EXPERIMENTATION, PARTICIPANTS

1.1. Site of experimentation

SPINCONTROL ASIA Co., Ltd. 483, 485 Soi Ladprao 101, Ladprao Road, Wangthonglang, Wangthonglang, BANGKOK 10310, THAILAND Phone: (+662).370.2688, 370.2589, 370.2740 - Fax: (+662).370.2418 E-mail: [email protected]

1.2. Study Sponsor

LIPOTEC SA C/Isaac Peral 17, Poligon Industrial Cami Ral, 08850 Gavà, BARCELONA, SPAIN

1.3. Study Monitor

Mrs. Montserrat MANGUES Date: Documentation and Regulatory Affairs Manager Signature:

Cosmetic Division, LIPOTEC SA Phone: (+34).93.638.8000 - Fax: (+34).93.638.9393 E-mail: [email protected]

1.4. Investigator

Mr. Fabrice PERIN Manager – Ph.D. Date: SPINCONTROL ASIA Co., Ltd. Signature: Phone: (+662).376.0929 E-mail: [email protected]

1.5. Study Manager

Ms. Paweena PUNGPOD Date: Technician - Bsc of Biology Signature: SPINCONTROL ASIA Co., Ltd. E-mail: [email protected]


1.6. Technicians

Mr. Kamolchai SAETUN Date: Technician - Bsc of Microbiology Signature: SPINCONTROL ASIA Co., Ltd. Ms. Jadesadaporn RUNGCHAROEN Date: Technician - Bsc of Agricultural Industry Signature: SPINCONTROL ASIA Co., Ltd.

1.7. Quality Assurance

Mrs. Christine PERRIER Date: Quality Assurance Manager Signature: SPINCONTROL 238, rue Giraudeau, 37000 TOURS, FRANCE

Ms. Jutatip BOONGIRD Date: Quality Auditor Signature: SPINCONTROL ASIA Co., Ltd.


2. SUMMARY OF THE STUDY

2.1. Objective The objective of this study will be to evaluate and to compare the in vivo effects of two whitening products on healthy Asian female subjects. The evaluation will be performed using:

Chromametry (measurement of the color of the skin with a chromameter CR-300®, Minolta,

Japan).

2.2. Population Twenty (+2) healthy Asian female subjects, 18-65 years old, all skin types, will be selected for this study.

The selection will be done according to the inclusion/exclusion criteria listed in paragraph 3.1.

2.3. Study design Randomized double-blind study; Comparative test (placebo-controlled split-face study); Subjects will serve as their own references.

2.4. Study schedule and duration The study will begin on May 30, 2007 and will end on July 27, 2007. Evaluations will be carried out according to the schedule presented below: Scheduled Procedures:

T0 T+1 month T+2 months

Dates 30/05 and 01/06/07 28-29/06/07 26-27/07/07

Chromametry End of the

study


Intermediate results (at T+1 month) will be given to the Study Monitor for July 16, 2007. Final results will be given to the Study Monitor for August 13, 2007. The final study report will be sent for August 28, 2007.


3. MATERIALS AND METHODS

3.1. Selection of the subjects Spincontrol Asia’s subjects’ panel is composed of subjects selected on the basis of a questionnaire filled in on a computer prior to the study that provides details of their medical history and possible allergies, skin-care and make-up habits, as well as a certain amount of administrative information. The recruitment and selection procedures are elaborated in order to guarantee that the subjects receive all possible information about the aims of the study and the consequences of their participation. This recruitment procedure includes: A preliminary interview during which the following points are explained to the subjects: the

study’s modalities, its practical considerations, possible emolument, as well as any possible cosmetic benefits, inconveniences or potential risks;

The information form which is specific to the study, including all essential information is then read;

The consent form is read, approved, and signed by the subjects to substantiate the fact that they freely accept the conditions of the study which have been described to them;

This consent form which is filled in freely and intentionally by the subjects after it has been fully explained to them, in the event of any claims for damages, enables them to benefit from the terms of the insurance policy taken out by the study sponsor.

The subjects recruited for the study are selected under the supervision of the investigator, on the basis of the inclusion/non inclusion criteria listed below. A selection of 20 subjects will be made for this study. In case subjects withdraw from the study, 2 additional subjects will be included. The results given will include all of the present and assessable subjects at the end of the study.

3.1.1. Inclusion criteria

The study will be conducted on subjects who fulfill the following criteria: Asian; Healthy; Female; 18-65 years old; Not using whitening/lightening/anti-dark spots products during the 6 weeks prior to the

beginning of the test; Available for the entire study duration (2 months); Motivated to freely participate in the study; Without any skin hypersensitivity or allergy to cosmetic products;


Not pregnant or not breast-feeding a child and committing herself not being pregnant during all the study;

Not having changed her cosmetic habits since at least 15 days; Not having used any treatments (medicinal, hormonal, dermatological) in the past 2 months; Not being in a non-inclusion period for the studied areas, at the beginning of the study,

because of an other previous cosmetic, dermatological or medical test; Having a healthy skin on the face (free of psoriasis, erythema, edema, scars, wounds); Being willing to follow the full products application procedure.

3.1.2. Exclusion criteria

Failing to meet the inclusion criteria listed above; Simultaneously participating in different biomedical research projects offering no direct

individual benefit and participating in any other studies while on this one; Non-respect of the non-inclusion period during which the subject cannot participate in any

other biomedical research projects offering no direct individual benefit; Having participated in skin or peri-ocular tolerance testing during the past two weeks and/or

in sensitization trials within the past four months; Individuals sentenced to imprisonment by a court decision or in need of urgent care due to

serious illness; Minors as well as individuals of age who are wards of the court, or mentally or physically

handicapped individuals insofar as the study can be undertaken in some other manner; Anyone who has any dermatological disease(s), or any other acute or chronic diseases; The refusal to give her assent by signing the informed consent form.

3.1.3. Proscriptions and restrictions The use of aspirin or products containing aspirin, anti-inflammatory medication or anti-

histaminic agents, or any treatment using corticosteroids taken orally, will be proscribed during the entire duration of the study;

The utilization of any other whitening/lightening/anti-dark spots products on the face will be proscribed during the entire duration of the study;

Exposing herself intentionally to the sun or making any UV will be proscribed during the entire duration of the study.

3.2. Description of the products The test products will be supplied free of charge by the study sponsor. The products will be creams, packaged in 80 grams jars. One product will be the active sample. One product will be a placebo. The study sponsor will be in charge of products manufacturing and packaging. He will be responsible for products identification, purity determination, composition, innocuousness, and any other characteristics of each product to be tested prior to the beginning of the study. The study sponsor supplied a non-toxicity certificate for the tested products.


References of the test products:

Product W1 (batch U18E1-07) versus Product W4 (batch U21E3-07) The study sponsor is responsible for supplying the exact amount of products needed to undertake the testing. The products should be delivered to the study manager 3 days prior to the beginning of the study at the latest. Should there be a delay in this delivery time due to the study sponsor’s responsibility, another time must be arranged between the two parties. For this study, the study sponsor agrees to supply: The appropriate quantity of products required to treat all the subjects; A sufficient quantity of products for any additional subjects participating in the study; One product unit per reference and per batch to be retained in the Reference Products

Cabinet. Products will be stored at ambient temperature, protected from contacting with air, light, heat and moisture.

3.3. Modalities of utilization of the products, randomization Each product will be applied on one randomly selected half-face twice daily, in the morning and in the evening, over a 2 month- period, by the subjects themselves. Products will be randomly assigned to the subjects in a manner which will be balanced for right and left half-faces across the panel. This randomization will be undertaken by a software designed for this purpose. Subjects shall prevent any solar exposure or UV exposure during the study, apart from their usual habits. They will be instructed to use a sunscreen (SPF 15 minimum) if they can not avoid occasional exposure. Test products weights will be measured at each visit in the test center to ensure that the appropriate amounts of test materials are being used. Subjects will be instructed not to use any other types of cosmetic creams or products on the face (in particular other whitening/lightening/anti-dark spots products) during the entire study. A subject declaration form will be distributed to each subject at T0, checked at each visit and collected back at the end of the test in order to monitor the compliance of the subjects regarding to the products application.

3.4. Cutaneous acceptability, adverse events Any major or unexpected adverse effects will immediately prompt the subject showing any intolerance whatsoever to stop application of the product(s) (an adverse event is defined as any expression of unwanted symptom felt or observed by the subjects, related or unrelated to the tested product(s)). Any major adverse effect shall be reported to the study monitor within 48 hours and confirmed in writing within three days.


Any incident occurring during the study will be recorded by the study manager in the study file. The nature, severity, date of appearance, duration, end date, any symptom assessment and any possible treatment will be described in the observation records as well as the possible cause of the unexpected effect. In case of emergency, the investigator will initiate the appropriate medical treatment. Despite such a treatment, should severe skin problems develop following application of the test product(s), the study sponsor takes responsibility for the financial cost of the dermatological or medical follow-up of the subject in question.

3.5. Withdrawal from the study A subject accepted into the study may be withdrawn or considered to have “dropped-out” if: A side effect attributable to the product(s) is judged severe by a dermatologist of a physician; The subject develops a systemic illness (without being related to the product(s) used in the

study but occurring during the study) and has to take contraindicated medication which is likely to influence the test measurements;

The subject does not respect the protocol. The subjects are entitled to drop out of the study at any time if they so desire (should this occur, the study manager will determine the reasons in order to know if it is linked to the study or not).

3.6. Discontinuance of the study The study sponsor may halt the study at any time for one of the following reasons: Impossibility of recruiting enough subjects; Protocol violations; Incomplete or imprecise data.

The investigator may also interrupt the study at any time in case of serious skin problems that involve risks to the subjects.

3.7. Technical equipment

If technical incidents involving the equipment occur, the study will be postponed rather than cancelled until the equipment is functioning again, with the consent of the study sponsor.

3.8. Study design This study will be carried out as a double-blind, split-face test and neither the participating

subjects nor the technicians in charge of data collection and evaluations will be aware of the type of product (active or placebo) being applied on each half-face;


This will be a comparative placebo-controlled study (active versus placebo). Results from the skin treated with the active product will be compared to those from the skin treated with the placebo product;

The subjects will serve as their own references.

3.9. Chromametry measurements Localization of the measurement areas and their locations at the different moments of the kinetics must be the most rigorously reproducible. The different measurements will be done on the left and right cheekbones, for each subject, on sites defined using a gabarit (a transparent overlay used to map the cutaneous features to help us to relocate precisely the measuring sites during all the study). The localizations of the measuring sites will be copied out on the observation record.

Figure 1: Illustration of the localization of the treated and measured site on the right cheekbone.

3.9.1. Principle The chromametry principle consists in simulating the perception of colors with the human eye. Chromameters use the tristimulus sensitivity that measures light so as to correspond to the human eye sensitivity. The concept of the tristimulus XYZ values comes from the theory according to which the perception of colors by the eye is made through 3 components (red, green and blue) and all the colors are perceived as a blending of these 3 colors. The Commission Internationale de l’Eclairage (C.I.E.) defined in 1931 a standard observer possessing the functions with the blending of x (λ), y (λ) and z (λ) that enables the calculation of tristimulus values. Tristimulus chromameters are made of a control unit and of a measurement headline. The headline measurement has a light with a pulsed xenon arch lamp which gives out an intense white light covering the whole visible spectrum (standard light). To compensate any difference of light provided by the pulsed xenon arch lamp, the headline contains a double beam system with a return coupling that measures at the same time the incident light and the reflected light. The color of the reflected light is analysed by 3 high-sensitive silicium photocells which are filtered to equal the curves of the standard observer of the CIE for the primary colors: blue (450 nm), green (550 nm) and red (610 nm). Three other identical filtered photocells are used for the back control system. Thus the photodiode system stimulates the answer of the human eye-brain system. Colors can be classified by their hue, luminosity and saturation. Any color can therefore be characterised in a space where geometric co-ordinates can help to determine brightness, dominant coloring and saturation level. Several spaces of different colors exist, mathematic links


making possible the conversion of the co-ordinates from one to another. In the color space L*a*b*, L* expresses brightness on a scale ranging from 0 for the black to 100 for the white. Hue and saturation are expressed by the combination of the chromaticities a* and b*.

3.9.2. Measurements The material used for this study will be a chromameter CR-300® (Minolta, Japan). This apparatus is a tristimulus color analyser, made up of a headline associated with a DP-301 calculator. The headline carries out the measures over an 8 mm diameter area and uses a diffuse light with a pulsed xenon arch lamp D65, as well as a sample reading of 0° (specular component included). Before each measurement time, the chromameter will be calibrated on a white ceramic plate, provided by the constructor and usually calibrated by this latter. Measurements will be performed after a 20 minute- period of rest in a controlled environment (20-24 °C, 40%<RH<60%). At each time of the kinetics and for each side (left and right half-face), 5 acquisitions will be made. These 5 measurements will be rigorously made at the same location at each time. The results will be expressed in the color space L*a*b* (L*: luminance; a*: red-green axis; b*: yellow-blue axis). Measurements will be performed throughout the study on the treated and placebo sites (at T0, T+1 month, and T+2 months).

3.9.3. Evaluation parameters The following parameters will be used to evaluate the in vivo effects of the tested products on the color of the skin: L* (Luminance) which represents the relative brightness from total darkness (L*=0) to

absolute white (L*=100); a* (red-green color axis); b*(yellow-blue color axis).

Mean values from 5 successive measurements will be calculated. Then from these three co-ordinates will be calculated the following parameters: ΔL*, Δa*, Δb*, and ΔITA° between T0 and each of the following time points. Where ITA° = Arctg [(L*-50)/b*].(180/π) is the Individual Typological Angle. All these parameters will be determined for the two measured sides of the face.

3.9.4. Interpretation of the chromametry parameters

The best description of a whitening effect is given by combining the L* and b* parameters, as described above, in the so-called Individual Typology Angle ITA° (Petit L, Pierard GE. Skin-lightening products revisited. International Journal of Cosmetic Science, 2003; 25: 169-181).


Therefore L* and ITA° were considered for the assessment of the whitening-lightening effect, the more the skin is light, the more the L* and ITA° values are high.

3.10. Examination schedule The effects of the products will be evaluated over a 2 month- period. The scheduled measurement procedures will be as follows: At T0 (Baseline evaluation before the use of the products): Reception, reading and signature of the consent form; Checking of the inclusion/non inclusion criteria and of the quality of the skin on the face; Acclimatization during 20 minutes; Measurements of skin’s color on the measuring sites (1 site per treated half-face) using the

chromameter CR-300®; Weighing of the test products; Distribution of the test products, of the Subject Declaration form (monitoring of compliance

of treatments between T0 and T+2 months) and of the Information notice. At T+1 month: Acclimatization during 20 minutes; Checking of the instructions and of the quality of the skin on the face; Interview about the subject’s tolerance of the products; Weighing of the test products; Measurements of skin’s color on the measuring sites using the chromameter CR-300®.

At T+2 months: Acclimatization during 20 minutes; Checking of the instructions and of the quality of the skin on the face; Interview about the subject’s tolerance of the products; Collecting of the remaining test products and of the subject declaration form; Weighing of the test products; Measurements of skin’s color on the measuring sites using the chromameter CR-300®; End of the study.

3.11. Data analysis and statistics Mean values (+/- standard deviation) will be calculated, as well as variations of the parameters relative to T0 values (expressed in %). Paired two-tailed Student’s t test will be used to determine the significance of the results, the level of significance being set at 5%.

This test will be applied to raw-data values, as well as to the evolution in the various parameters over the entire duration of the study (compared to T0).


4. ETHICAL AND LEGAL CONSIDERATIONS

4.1. Study personnel The investigator asserts that the study manager and all the persons who will participate in this study have the required qualifications and abilities to carry it out.

4.2. Archiving of the data Dual archiving is ensured by using both paper and IT storage media: paper files are kept in a locked archiving room. The investigator will keep a copy of the protocol signed by both himself and by the Study Sponsor, as well as the original “observation records” (and all associated documents), the participation consents, and all project-related documents of any type for a 10-year period following delivery of the final reports. All these documents will be accessible upon request for inspection by the study sponsor or their representative. The investigator will inform the study sponsor of his intention to proceed with their destruction after the 10-year period.

4.3. Amendments to the protocol Each amendment will mention a number of amendments and the date of its realization. The references of the modified paragraphs will appear in the amendment. To accept one amendment, the Study Sponsor and the Investigator will have to sign it. The study sponsor is hereby informed that any modification requiring a protocol amendment leads to additional costs.

4.4. Anonymity of the subjects The subjects will be identified for the study sponsor using a five-character alphanumeric code.

4.5. Consent to participate in the study An information form is given to each subject providing full details about the study and: Its objectives, methods, and duration; Possible expected benefits, constraints, and potential risks (especially should the study be

discontinued);


The non-inclusion period, the amount of the emolument, the right of access to data files and their later destruction.

This information enables the subjects to sign their participation consent forms freely and unequivocally, in the knowledge that they are fully aware of testing details.

4.6. Confidentiality All the information, data, and results of the study are confidential. All persons having access to such data will be informed about their confidentiality. Medical information obtained by the investigator during the recruitment and admission procedures will be handled confidentially. Nominal information of this type shall not be transmitted to the study sponsor. But in cases of adverse event reactions, data will be given to the study sponsor. The investigator and individuals conducting the testing are bound by professional secrecy concerning the nature of the products under study, the trials, the subjects, and the final results.

4.7. Study incidents Any incidents occurring during the study will be promptly reported to the study monitor. Both parties agree that they will immediately inform one another in case of unanticipated problems that hinder the study. They will decide of any changes or modifications required in order to continue the testing by mutual agreement. If they do not arrive at an agreement, the study sponsor has the right to halt the study by notifying the investigator by registered letter. In this event, the cost of the study amounts to the trials that have been effectively performed prior to this interruption. All advance payments made in excess of this amount are refunded to the study sponsor.

4.8. Quality Assurance The entire file (protocol, study-related documents, photographs, report) will be subject to quality assurance procedures. The protocol will be audited. Specific procedures and data from this study will be controlled. Other relevant procedures and data are also checked periodically. The final report will be reviewed to ensure that it accurately describes the methods and procedures, and that the results accurately reflect the raw data. Reports on these activities will be made to the Study Director and to the Management. The investigator will cooperate in ensuring any additional auditing required by the study sponsor with regard to the protocol or the current procedures.


Reports Incidental reports: the study sponsor will be informed promptly of any significant findings at

any time during the study; Draft reports: complete draft reports in English, audited by the Quality Assurance Unit and

containing all procedures and results will be issued for discussion with the study sponsor; Final reports: after reciprocal agreement the final report will be issued and sent to the study

sponsor with a summary in English. This report will include all the details with the following additions:

- The signature of the study director and other Scientifics involved in the study as authentification of the report;

- A statement that the reports have been subjected to QA Evaluation.

4.9. Regulations This study, which has no direct therapeutic purpose, will be undertaken according to the most recent recommendations given by the World Medical Association (Helsinki Statement 1964, amended in Edinburgh, Scotland, 2000).

4.10. Practical considerations A preliminary agreement between the Investigator and the study sponsor, concerned by the present contract, is necessary for any publication or communication directly concerning the two parties. They must both take the initiative to inform each other if a change is to occur.


APPENDIX 1

RANDOMIZATION SHEET


CodeW1 W4

Right LeftLeft Right

Right LeftRight LeftLeft Right




Right LeftLeft RightLeft RightLeft RightLeft Right



W1 W4Right 11 11Left 11 11

Advent frequency

1617181920

22

Randomization sheet C03-PF02-LP-MI07Product Half-face Subjects

4567

22

123

Subject number Randomization

W1W4

RightLeft

8

13

9101112

1514

21


APPENDIX 2

OBSERVATIONS RECORD


OBSERVATIONS RECORD Ref.: C03-PF02-LP-MI07(V01)




Product W1 versus Product W4

In vivo test on subjects INVESTIGATOR:

Mr. Fabrice PERIN Managing Director – Ph.D. SPINCONTROL ASIA Co., Ltd.

SUBJECT NUMBER :

AGE (years):

F


T0 DATE: _ _ / _ _ / 07

SUBJECT NUMBER:

INCLUSION CRITERIA

• Asian female subject: YES NO • Are you in good health? YES NO • 18-65 years old YES NO • Skin at assessed areas is healthy (free of psoriasis, eczema, erythema, edema, scars,

wounds or lesions) YES NO

• Without any skin hypersensitivity or allergy to cosmetic products YES NO • Not having used whitening/lightening/anti-dark spots products during the last 6

weeks YES NO

• Are you available for the entire duration of the study (2 months)? YES NO • Are you motivated to freely participate in the study? YES NO • Are you willing to follow the full products application procedure? YES NO • Not having used any treatments (medicinal, hormonal, dermatological) in the past 2

months YES NO

To be included into the study, all the responses « YES » have to be circled except particular case approved by the study manager. If no, justifications ………………………………………………………………………………………

EXCLUSION CRITERIA • Are you pregnant or did you breastfeed a baby in the past 3 months? YES NO • Do you intend to become pregnant during the study? YES NO • Did you modify your cosmetic habits these last 14 days? Do you intend to change them

during the study? YES NO

• Being in a non-inclusion period, at the beginning of the study, on the studied area(s), because of another cosmetic, dermatological or medical test YES NO

• Simultaneously participating in different biomedical research projects offering no direct individual benefit and participating in any other studies while on this one YES NO

• Do you have dermatological disease(s), or any other acute or chronic diseases? YES NO • Have you participated in skin or peri-ocular tolerance testing during the past two weeks

and/or in sensitisation trials within the past four months? YES NO

• Refusal to give their assent by signing the informed consent form? YES NO To be included into the study, all the responses « NO » have to be circled except particular case approved by the study manager. If no, justifications ………………………………………………………………………………………… INCLUSION OF THE SUBJECT: YES NO

Signature of the technician:

F


T0 DATE: _ _ / _ _ / 07

SUBJECT NUMBER:

ACCLIMATIZATION

20 minutes of acclimatation: Temperature (20-24) °C: _________ Hygrometry (50±10) % : ___________

Hour of arrival in air-

conditioned room

Hour of acquisition

(Photographs)

Respect of the 20 min of rest period Circle the answer

T0 _ _ : _ _ _ _ : _ _ YES NO

If no, precise: …………………….........................................................................................….

CHROMAMETRY AT T0

Ref. Equipment : Chromameter CR300® (Minolta, Japan)

5 measurements per site (5 seconds between each measurement)

Temperature (20-24 °C): ………°C Hygrometry (40-60% RH): ……… % RH

Calibration done before the beginning of the experimental measurements, is conform and has been registered in the record of in-house and external calibration (Chromameter CR300®):

□ YES □ NO

Transparent overlay – Locating of measured sites recorded □ YES □ NO

Recording: XXXX-LF-00 (Subject number-Left Half-Face-T0) LEFT HALF-FACE

Time Recording T0 done

Recording: XXXX-RF-00 (Subject number-Right Half-Face-T0) RIGHT HALF-FACE

Time Recording T0 done

F


T0 DATE: _ _ / _ _ / 07

SUBJECT NUMBER:

Weight of the test product W1: _ _ _ _ _ _ _ _ _ grams


Distribution of the products: YES NO Distribution of the information form: YES NO

Distribution of the subject declaration form: YES NO


F


T+1 MONTH DATE: _ _ / _ _ / 07

SUBJECT NUMBER:

CHECKING OF THE INSTRUCTIONS

• Use of aspirin or products containing aspirin, anti-inflammatory medication or anti-histaminic agents, or any treatment using corticosteroids taken orally, during the study YES NO

• Intentional sun or UV exposure YES NO • Did you use another whitening/lightening/anti-dark spots product on the face during

the study except the tested product? YES NO

• Did you follow another cosmetic, dermatological or medical treatment liable to interfere with this study during the study? YES NO

• Important protocol deviation/transgression YES NO To be kept in the study, all answers must be NO except particular case approved by the study manager If no, justifications: ……………………………………………………………………………………………………

EXCLUSION OF THE SUBJECT: YES NO

ACCLIMATIZATION



conditioned room

Hour of acquisition

(Photographs)


T+1 m. _ _ : _ _ _ _ : _ _ YES NO

If no, precise: …………………….........................................................................................….

CUTANEOUS ACCEPTABILITY AT T+1 MONTH

Adverse or undesirable event reported by the subject: YES NO If yes, complete the Adverse Event Form (last page of CRF)

F


T+1 MONTH DATE: _ _ / _ _ / 07

SUBJECT NUMBER:



Checking of the subject declaration form: YES NO


CHROMAMETRY AT T+1 MONTH





□ YES □ NO


Time Recording T+1 m. done



F


T+2 MONTHS DATE: _ _ / _ _ / 07

SUBJECT NUMBER:

CHECKING OF THE INSTRUCTIONS

• Use of aspirin or products containing aspirin, anti-inflammatory medication or anti-histaminic agents, or any treatment using corticosteroids taken orally, during the study YES NO

• Intentional sun or UV exposure YES NO • Did you use another whitening/lightening/anti-dark spots product on the face during

the study except the tested product? YES NO

• Did you follow another cosmetic, dermatological or medical treatment liable to interfere with this study during the study? YES NO

• Important protocol deviation/transgression YES NO To be kept in the study, all answers must be NO except particular case approved by the study manager If no, justifications: ……………………………………………………………………………………………………

EXCLUSION OF THE SUBJECT: YES NO

ACCLIMATIZATION



conditioned room

Hour of acquisition

(Photographs)


T+2 m. _ _ : _ _ _ _ : _ _ YES NO

If no, precise: …………………….........................................................................................….

CUTANEOUS ACCEPTABILITY AT T+2 MONTHS

Adverse or undesirable event reported by the subject: YES NO If yes, complete the Adverse Event Form (last page of CRF)

F


T+2 MONTHS DATE: _ _ / _ _ / 07

SUBJECT NUMBER:



Collecting of the test products: YES NO

Checking and collecting of the subject declaration form: YES NO


CHROMAMETRY AT T+2 MONTHS





□ YES □ NO





F


STUDY REF. C03-PF02-LP-MI07 ADVERSE EVENT REPORT SUBJECT NUMBER:

Information about the adverse event Description:

□ Left half-face □ Right half-face

Intensity: □ Mild □ Moderate □ Severe

Duration: Began on: Ended on: □ Not resolved

Frequency:

□ At 1st application / Use □ At repeated applications / Use

□ Immediate □ Delayed

□ Transient □ Persistent

Measure undertaken: Precise: □ None □ Temporary interruption of the treatment □ Definitive interruption □ Corrective treatment □ Diminution of the dosage □ Medical examination

Evolution: □ Recovery □ Improvement □ Aggravation □ No change □ Aftereffect

Precise: Date resolved:

Relationship between the tested product(s) and the observed or reported adverse event:

Disappearance of the event after interruption of the treatment:

□ Yes □ No □ Not assessable

Reappearance of the event after reintroduction of the treatment:

□ Yes □ No □ Not assessable

Test product exposure: Use began on: Use ended on: Number of uses:

Changing in the subject habit:

Pertinent medical history (e.g., causes of similar reactions, known allergies…): Patch test: □ Yes □ No Conclusion: The latest date, causes and duration when similar reactions occurred: Date: Duration: Causes: Relationship: □ None □ Unlikely □ Possible □ Certain □ Not assessable Reason:


APPENDIX 3

SUBJECT DECLARATION FORM (English and Thai versions)


SUBJECT DECLARATION FORM for the study reference C03-PF02-LP-MI07 Subject F - - - - - For different reasons, during the study time course, you have not respected the study protocol concerning the regularly utilization of the tested products.

Thank you to complete the more rigorously possible the table(s) corresponding to you personal reason(s). 1) FORGETTING: FORGETTING (if different products tested, please precise)

Date - - / - - / - - - - / - - / - - - - / - - / - - - - / - - / - - - - / - - / - -

When Morning - Evening Morning - Evening Morning - Evening Morning - Evening Morning - Evening NOTE: Circle the good answer

2) OBSERVATION OF UNDESIRABLE ADVERSE EVENT(S) and FOLLOW-UP:

Use Effect Effect Duration Intensity Use interruption? Medical examination? Evolution Comedo At 1st use

At repeated uses Immediate Delayed

Transient Persistent

Began on -- / -- / -- Ended on -- / -- / -- Not resolved

Mild Moderate Severe

YES, temporarily YES, definitively NO

YES (Date : - - / - - / - - ) ……………………………..

NO

Recovery, Improvement No change Aftereffect, Aggravation

Cutaneous dryness At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Desquamation At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Feeling of warmth At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Itching, Tickling At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Rash At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Redness At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO


Other (precise) -----------------------------

At 1st use At repeated uses

Immediate Delayed





YES (Date : - - / - - / - - ) ……………………………..

NO



แบบฟอรมติดตามผลการใชผลิตภัณฑ ของการวิจัย C03-PF02-LP-MI07 หมายเลขอาสาสมัคร F - - - - - ในชวงระยะเวลาการทดสอบ หากทานไมสามารถปฏิบัติตามกฎเกณฑในการใชผลิตภัณฑได กรุณากรอกหรือเลือกคําตอบในตารางใหสมบูรณในขอทีต่รงกับเหตุผลของทาน ขอขอบคุณ

1) กรณีลืม:

กรณีลืม (ถาลืมใชผลติภัณฑตางชนิดกัน กรุณาระบุชนิดผลิตภัณฑที่ลืมใช)

วันที่ลืม - - / - - / - - - - / - - / - - - - / - - / - - - - / - - / - - - - / - - / - -

เมื่อไหรที่ลืม เชา - กอนนอน เชา - กอนนอน เชา - กอนนอน เชา - กอนนอน เชา - กอนนอน

หมายเหต:ุ ใหวงกลมคําตอบที่ใช 2) ขอมูลของอาการขางเคียงและผลที่เกิดขึ้น:

ครั้งที่ใชแลวเกิดอาการ เริ่มเปนเมื่อ ระยะเวลา ชวงเวลา ความรุนแรง มีการหยุดใชหรือไม ไดรับการตรวจจากแพทยหรือไม ผลที่เกิดขึ้น สิว ครั้งแรกที่ใช

ครั้งตอไปที่ใช ทันที สักพัก

ชั่วคราว คงอยูนาน

เริ่มเมื่อ -- / -- / -- สิ้นสุดเมื่อ -- / -- / -- ไมหาย

เล็กนอย ปานกลาง รุนแรง

ใช, หยุดชั่วคราว ใช, หยุดถาวร ไม

ใช (วันที่ : - - / - - / - - ) …………………….

ไม

อาการหายไป, ดีขึ้น ไมเปลี่ยนแปลง มีผลกระทบ, รุนแรงขึ้น

ไมสบายผิว ผิวแหง ครั้งแรกที่ใช ครั้งตอไปที่ใช

ทันที สักพัก





ใช (วันที่ : - - / - - / - - ) …………………….

ไม


ผิวลอกเปนขุย ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม


รูสึกรอนผิว ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม


คัน ระคายเคือง ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม


ผื่น ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม


เกิดรอยแดง ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม


อื่น (กรุณาระบุ) -----------------------------

ครั้งแรกที่ใช ครั้งตอไปที่ใช






ใช (วันที่ : - - / - - / - - ) …………………….

ไม



APPENDIX 4

CONSENT TO PARTICIPATE (English and Thai versions)


CONSENT TO PARTICIPATE

Of M ………………………………………………………………………..... (Name and First name) Residing at the following address…………………………………………………………………… ………………………………………………………………………Phone. : . . . . . . . . . . . . . . . . . . .

EVALUATION OF THE EFFICACY OF TWO COSMETIC PRODUCTS

Mr Fabrice PERIN (Managing Director of SPINCONTROL ASIA Co., Ltd.), has suggested I might be willing to participate in testing cosmetic products. I have received and understood the following information: This study will be carried out at the head office of the SPINCONTROL ASIA Company (483, 485 Soi Ladprao 101, Ladprao Road, Wangthonglang, Wangthonglang, BANGKOK 10310). I know that: • The products only contain raw materials that comply with the legislation in force covering

cosmetic and hygiene products and that it has been normally subjected to the preliminary harmlessness tests required prior to launch any effectiveness testing;

• I must warn SPINCONTROL ASIA CO., LTD. if I am undergoing a medical treatment, have had an accident, or any other reasons which may interfere with the study or necessitate my stopping of the treatment.

I’ve learned about the information and instructions corresponding to the study from the document ref. C03-PF02-LP-MI07-IF, and I commit to respect it. • The nature of the test, its purpose and possible inconveniences have been explained to me by the

investigator in charge of this test. I have received a satisfactory answer to all the questions I was able to ask freely concerning this test. I received information about the products, the objectives, the practical realization and the potential risks of the test. I am perfectly aware of the fact that the test to which I will be subjected is purely experimental and that I cannot expect any benefit with regard to my health;

• I agree to heed all the instructions I receive from the investigator, particularly as concerns the regularity of products application and not using any other product, apparatus, medical treatment which can interfere with the study;

• I agree to relate any symptoms that seem abnormal to the investigator, whether or not they are related to the test;

• I freely accept my participation in this test without being under any type of pressure. I know that I may decide at any time to interrupt the test without any prejudice for me. In that such case the expected remuneration won’t be given to me;

• I accept the fact that the data recorded in the course of this test may be processed electronically by the investigator for the counting of the study sponsor;

• The medical information obtained by the investigator will be handled confidentially. I authorize access to it only to those individuals who are involved in the research and who have been designed by the investigator;

• I give my consent for the brief to be consulted by the study sponsor. I declare that: • I’m not pregnant or breast-feeding a child and I commit myself not being it during all the study;


• I’m not in remanence on the studied areas, at the beginning of the study, because of another cosmetic, dermatological or medical test;

• The information I provided during my registration in the volunteers database were accurate; • I am not simultaneously engaged in any therapeutic or non-therapeutic tests; • I am covered by health insurance policy; • I commit to keep confidential all information which will be given to me concerning the study

and the product; • I agree to heed the protocol (Dates and times of the appointments, application of the products); • I agree to comply with the regulations of the centre where the test is undertaken; • I have been informed about the manager’s absolute right to interrupt the testing should he

believe it may be harmful to the participant without the latter being compensated under the circumstances;

• I have been informed that the investigator will retain the present document in conditions guarantying its confidentiality and I consent. I have received a copy;

• I can justify of a fixed address; • I am not in the following situations:

• Subject without freedom by a court or administrative rulings, sick in emergency situation; • Minor or major subject protected by the law, and them who are admitted in a social or health establishment, at the moment the research can be made differently; • Participating simultaneously to several biomedical research studies; • Having participated to another test for checking cutaneous or peri-ocular local tolerance for the two last weeks and / or participated to a test of sensitization since 4 months.

I agree to respect the proscriptions and restrictions described in the document ref. C03-PF02-LP-MI07-IF.

I ACCEPT PARTICIPATING IN THIS TEST UNDER THE CONDITIONS STIPULATED ABOVE. My consent does not relieve the test organizers of their responsibilities. I retain all right vested in me under the law. If I so desire, I am free to interrupt my participation at any time. If that was the case, I would inform Mr Fabrice PERIN. I may request further information at any time. Phone: (662) 370 2688, 370 2589 Date: . . . . . . . . . . . . . . . . . . Date: . . . . . . . . . . . . . . . . . Subject’s Signature Investigator’s Signature: (preceded by the statement « read and approved »):


ใบยินยอมเขารวมในการทดสอบ (สามารถขอเอกสารสําเนาได)

ผูเขารวมการทดสอบ.........................................................................................................................................................................ชื่อและนามสกุล ที่อยู..........................................................................................................................................................................โทรศัพท.....................................

นาย ฟาบรีส เปแรง (กรรมการผูจัดการบริษัท สปนคอนโทรล เอเซีย จํากัด) เปนผูควบคุมการทดสอบไดแนะนําขาพเจาในการเขารวมการทดสอบผลิตภัณฑเคร่ืองสําอาง ขาพเจาไดรับทราบและเขาใจรายละเอียด ดังน้ี: การทดสอบไดจัดทําขึ้นที่สํานักงานใหญ บริษัท สปนคอนโทรล เอเซีย จํากัด เลขท่ี 483, 485 ซอยลาดพราว 101 ถนน ลาดพราว แขวงวังทองหลาง เขตวังทองหลาง กรุงเทพฯ 10310.

ขาพเจารับทราบวา: • ผลิตภัณฑนี้ประกอบดวยวัตถุดิบที่อยูภายใตกฎหมายควบคุมเคร่ืองสําอางและสุขภาพที่ผานการทดสอบความปลอดภัยเบ้ืองตนกอนที่จะทํา

การทดสอบประสิทธิภาพ • ขาพเจาจะแจงเตือนใหบริษัทสปนคอนโทรล เอเซีย จํากัด ทราบ หากขาพเจาไดรับการรักษาทางการแพทย, ไดรับอุบัติเหตุ,หรือดวยเหตุผล

ใดๆ ก็ตามท่ีอาจมีผลรบกวนการศึกษา หรือจําเปนตองหยุดการทดสอบ ขาพเจาไดรับขอมูลและเคารพในขอบังคับเกี่ยวกับการศึกษาน้ีจากเอกสารขอมูลการวิจัยเอกสารแนบ C03-PF02-LP-MI07-IF

• ผูควบคุมการทดสอบท่ีรับผิดชอบการทดสอบนี้ไดชี้แจงลักษณะ, วัตถุประสงค, และความไมสะดวกที่อาจเกิดขึน้และตอบคําถามเปนที่นาพอใจเก่ียวกับการทดสอบ ขาพเจาไดรับขอมูลเก่ียวกับผลติภัณฑ, วัตถุประสงค, ขอควรตระหนักในทางปฏิบัติและความเส่ียงตางๆ ของ

การทดสอบ ขาพเจาตระหนักดีวาการทดสอบนี้เปนเพยีงการทดสอบและโดยมิไดคาดหวังผลตอบแทนใดๆ ที่เก่ียวกับสุขภาพของขาพเจา • ขาพเจายินดีปฏบิัติตามคําส่ังและขอแนะนําจากผูควบคุมการทดสอบ โดยเฉพาะที่เก่ียวกับวิธีการใชผลิตภัณฑ และจะไมใชผลิตภัณฑอื่นๆ,

เคร่ืองมือหรือการรักษาทางการแพทยที่อาจมีผลรบกวนการศึกษา • ขาพเจาจะแจงอาการหรือความผิดปกติใดๆ ไมวาจะมีผลเกี่ยวเน่ืองจากการทดสอบหรือไมก็ตามใหแก ผูควบคุมการทดสอบทราบ • ขาพเจาเขารวมการทดสอบโดยมิไดมคีวามกดดันใดๆ และสามารถหยุดการทดสอบไดทุกเวลาโดยไมมีอคติใดๆ และจะไมไดรับ

คาตอบแทนใดๆ ทั้งส้ิน • ขาพเจายินยอมใหผูควบคุมการทดสอบประเมินผลการทดสอบโดยใชเคร่ืองมือทางอิเล็กทรอนิค • ขอมูลทางการแพทยที่ไดโดยผูควบคุมการทดสอบจะถูกเก็บเปนความลับ และขาพเจายินยอมใหขอมูล ดังกลาวแกผูที่เก่ียวของกับการ

ทดสอบและผูที่ไดรับมอบหมายจากผูควบคุมการทดสอบ • ขาพเจาไดใหใบยินยอมเขาการทดสอบน้ีเปนขอมูลแกผูวาจาง ขาพเจาขอแจงใหทราบวา: • ขาพเจามิไดต้ังครรภหรืออยูในชวงใหนมบุตรและจะไมเปนตลอดชวงการศึกษา • ขาพเจามิไดอยูในชวงพักการทดสอบบนบริเวณที่ทดสอบ หรือเขารวมการทดสอบอื่นๆ ทางดานเคร่ืองสําอาง, ผิวหนังหรือการทดสอบทาง

การแพทย อื่นๆ เมื่อเร่ิมการศึกษา • รายละเอียดหรือขอมูลใดๆท่ีขาพเจาไดแจงไวในการลงทะเบียนอาสาสมคัรเปนความจริงทุกประการ

การทดสอบประสิทธิภาพของเคร่ืองสําอาง


• ขาพเจามิไดเขารวมการทดลองบําบัดรักษาโรคหรือการทดสอบท่ีมิใชการบําบัดใดๆ • ขาพเจาอยูภายใตการคุมครองของกฎหมายประกันสุขภาพ • ขาพเจาจะเก็บรักษาขอมูลที่ไดเก่ียวกับการทดสอบและผลิตภัณฑเปนความลับ • ขาพเจาจะปฏิบัติตามขั้นตอน (วัน, เวลาการพบ และการใชผลิตภัณฑ) อยางเครงครัด • ขาพเจาจะปฏิบัติตามขอกําหนดของสถานท่ีที่ทําการทดสอบ • ขาพเจาไดรับทราบวาผูควบคุมการทดสอบมีสิทธิยุติการทดสอบในกรณีที่เห็นวาอาจเกิดอันตรายและขาพเจาจะไดรับคาตอบแทนตาม

สัดสวนเวลาท่ีเขาทดสอบ • ขาพเจาทราบวาผูควบคุมการทดสอบจะจัดเก็บเอกสารนีเ้ปนความลับ และขาพเจาไดรับสําเนาเอกสารแลว • ขาพเจามีที่อยูที่ถาวร • ขาพเจามิไดอยูในสถานการณดังตอไปน้ี

o อยูภายใตคําส่ังศาลหรือกฎขอบังคับที่วาดวยการปวยฉุกเฉิน o มีอายุตํ่ากวา 18 ปที่อยูภายใตการคุมครองของกฎหมายและองคการทางสังคมหรือสุขภาพใดๆ o เขารวมการศึกษาวิจัยทางการแพทยตางๆ o เขารวมการทดสอบอื่นๆเก่ียวกับการตรวจสอบการแพมาในชวง 4 สัปดาหที่ผานมา และ/หรือเขารวมการทดสอบการเกิดภูมิแพ

ในชวง4 เดือนที่ผานมา ขาพเจาเคารพในขอหามและขอกําหนดดังอธิบายในเอกสารอางขอมูลการวิจยัดังในเอกสารแนบ C03-PF02-LP-MI07-IF ขาพเจาเขารวมการทดสอบนี้ภายใตเงื่อนไขดังกลาวขางตน สัญญาวาจางของขาพเจาน้ีมิไดลดความรับผิดชอบของผูจัดการทดสอบ สิทธิของขาพเจายังคงอยูภายใตกฎหมาย ขาพเจาสามารถยกเลิกการรวมทดสอบไดทุกเวลาที่ขาพเจาตองการ และในกรณีดังกลาวขาพเจาจะแจงให นายฟาบรีส เปแรง ทราบ

ขาพเจาสามารถขอรับทราบขอมูลตางๆไดทุกเวลาที่หมายเลขโทรศัพท (662) 370 2688, 370 2589

วันที่:................................................... วันที่: ...................................................

ลายมือชื่อผูเขารวมทดสอบ ลายมือชื่อผูควบคุมการทดสอบ: ...............................

(อานและตรวจทานแลว ):........................................


APPENDIX 5

SUBJECT INFORMATION FORM (English and Thai versions)


SUBJECTS INFORMATION FORM Ref.: C03-PF02-LP-MI07-IF

- Title: Evaluation of the in vivo efficacies of two whitening products by chromametry. - Place: SPINCONTROL ASIA Co.,Ltd. (483, 485 Soi Ladprao 101, Ladprao Road,

Wangthonglang, Wangthonglang, BANGKOK 10310). - Scope: To evaluate the efficacies of two whitening products by Chromametry on 20 (+2)

healthy Asian subjects. - Products: W1 and W4

- Products application:

Localization Application

Frequency of application

Duration of application Storage of the products

One product per Half-face

(according to the technician’s instructions

below)

Twice daily In the morning and

in the evening

2 months Normal conditions

LEFT HALF-FACE: Product _ _ _ _ _ _ RIGHT HALF-FACE: Product _ _ _ _ _ _

- Methodology:

Evaluation of the efficacy will be performed by:

o Chromametry (measurement of the color of the skin)

- Duration, Dates of the study:

Study duration: 2 months

3 appointments (T0, T+1 month and T+2 monthss)

Duration of the appointments: 1 hour


- Period of non-inclusion (remanence): I commit to respect a 2 months period during

which I will not engage myself in another study.

- Allowance: 900 Baths will be given at the end of the study if the protocol has been

respected. This allowance is offered to compensate the constraints related to the participation in the study. In case of absence, 300 Bahts will be deduced from the compensation per missed appointment.

- Instructions:

- Respect the conditions of application of the test products and the dates of appointments;

- Do not use other whitening/lightening/anti-dark spots products on the face; - Do not make UV and do not expose yourself intentionally to the sun; - Do not use of aspirin or products containing aspirin, anti-inflammatory medication or

anti-histaminic agents, or any oral treatment; - At each visit, bring back the remaining products and the subject declaration form.

- Let us know in cases of:

- cutaneous reaction or adverse events - if you are unable to come at one appointment - medical treatment, modifications of feeding habits or any changes in medications - any event likely to interfere with the study.

Note: In case of adverse event or unanticipated event, please inform us immediately. You will be advised and treated with free of charge.

THANK YOU!

SPINCONTROL ASIA CO., LTD - Tel: 02.370.2589, 02.370.2688 Contact: Ms. Paweena PUNGPOD or Mr. Kamolchai SAETUN

(In case of absence, leave a message)


เอกสารขอมูลการวิจัย หมายเลข (C03-PF02-LP-MI07-IF)

- ช่ือโครงการ การทดสอบประสิทธิภาพของผลิตภัณฑที่ทําใหผิวขาวขึ้นโดยใชเคร่ืองมือตรวจวัดสีผิว (โครมามิเตอร) - สถานที่ทดสอบ บริษัท สปนคอนโทรล เอเชีย จํากัด (เลขที่ 483, 485 ซอยลาดพราว 101 ถนน ลาดพราว แขวงวังทองหลาง เขตวังทองหลาง กรุงเทพฯ 10310) - รายละเอียดโครงการ การทดสอบประสิทธิภาพของผลิตภัณฑที่ทําใหผิวขาวขึ้นโดยใชเคร่ืองมือตรวจวัดสีผิว(โครมามิเตอร) ในอาสาสมัครหญิงเอเชีย สุขภาพดี 20 (+2) คน - ผลิตภัณฑ W1, W4

- วิธีทาผลิตภัณฑ

บริเวณท่ีทา ความถ่ี ระยะเวลาทดสอบ การเก็บผลิตภัณฑ

1 ผลิตภัณฑ ตอหน่ึงดานของใบหนา (ตามที่เจาหนาที่กําหนด)

2 คร้ังตอวัน ในตอนเชาและเย็น 2 เดือน อุณหภูมิหอง

หนาดานซาย : ผลิตภัณฑที่ทําใหผิวขาวขึ้น .................. หนาดานขวา : ผลิตภัณฑที่ทําใหผิวขาวขึ้น .................

- วิธีการทดสอบ ทําการประเมินประสิทธิภาพโดย:

• ใชเคร่ืองโครมามิเตอร (เคร่ืองมือตรวจวัดสีผิว ) - ระยะเวลาและวันที่ทําการทดสอบ

ระยะเวลาการทดสอบ 2 เดือน

นัด 3 คร้ัง (ที่กอนใชและหลังใชเปนเวลา 1 เดือน และ 2 เดือน)


ระยะเวลาการนัด - ชวงระยะพักการทดสอบ : ขาพเจายินยอมที่จะงดเขารวมการทดสอบอื่นๆ ในระยะเวลา 2 เดือนหลังจบการทดสอบน้ี - คาตอบแทน : คาตอบแทนจะให เม่ือปฏิบัติตามขอกําหนดจนส้ินสุดการทดสอบ เปนจํานวน 900 บาท หากอาสาสมัครไมสามารถมาตามนัดได คาตอบแทนจะถูกหักคร้ังละ 300 บาท - ขอกําหนด: - ปฏิบัติตามขอกําหนดวิธีใชผลิตภัณฑอยางเครงครัด และมาพบตามวันเวลาท่ีนัด - ไมใชผลิตภัณฑเคร่ืองสําอางที่ทําใหหนาขาว/กระจางใส/ลดกระ จุดดางดํา ตัวอื่นๆใบหนาในชวงการทดสอบ - ไมตากแดดหรือโดนแสงยูวีโดยไมจําเปน - ไมใชยาแอสไพริน หรือผลิตภัณฑที่มียาแอสไพรินเปนสวนประกอบ ยาแกอักเสบ หรือรับประทานยาอื่นๆ ที่จะมี

ผลตอการทดสอบ - สัปดาห ใหนําผลิตภัณฑ พรอมใบบันทึกกลับมาที่บริษัท - กรุณาแจงทางบริษัทใหทราบทันทีเมื่อเกดิเหตุการณดังตอไปนี้: - เกิดอาการผิดปกติของผิว เชน อาการคัน ,แสบแดง ,อื่นๆ - ไมสามารถมาตามเวลานัดได - รับการรักษา ,มีการเปล่ียนชนิดหรือปริมาณยา - เหตุการณตางๆที่รบกวนการทดสอบ หมายเหตุ : กรณีเกิดความผิดปกติใดๆ จากการเขารวมการทดสอบ ขอใหอาสาสมัครแจงบริษัทโดยเร็วที่สุด ทางบริษัท ยินดีใหคําแนะนําและดูแลอาสาสมัครโดยไมตองเสียคาใชจายใดๆ ทั้งส้ิน

ขอขอบคุณทีเ่ขารวมการทดสอบ บริษัท สปนคอนโทรล เอเชีย จํากัด โทรศัพท 0-2370-2688,0-2370-2589

ติดตอ: กมลชัย แซตัน (สามารถฝากขอความไว ในกรณีที่ไมสามารถติดตอได)

ประมาณ 1 ชั่วโมง


APPENDIX 6

RESUME OF THE INVESTIGATOR


Mr. Fabrice PERIN Born: June 27, 1968 Married 10 years of experience in the field of Cosmetic Science 15 articles in International Scientific journals 59 presentations in National and International Congresses EDUCATION

1994 Ph.D. in Biomedical Sciences (Faculty of Medicine of Tours, France) 1992 University Degree of Biomedical Nuclear Magnetic Resonance (Tours, France) 1991 University Degree of « Signals and Images in Biology and Medicine » (Tours,

France) 1989-1990 Bachelor in Sciences (University of Aix-Marseille, France) PAST PROFESSIONNAL EXPERIENCES

2003-2007 Managing Director (Spincontrol Asia Co., LTD) 1996-2003 Technical Manager in charge of clinical studies (Spincontrol company, Tours,

France) 1995-1996 Researcher : industrial projects and transfer of technology (Laboratory of

Biophysics and NMR, CNRS-INSERM U316, Tours, France) 1994 Researcher (Laboratory of Radio-Toxicology, CEA, Bruyères le Châtel, France) ADDITIONAL EXPERIENCES AND TRAININGS

2002 First-aid worker, rescuer 1995 Quality Assurance: accreditation, certification, Good Laboratory Practices procedures 1995 Quality Assurance (Pharmakon Europe, L’Arbresle, France) 1994 Radioprotection (INSTN, Saclay, France)

Spincontrol Asia Co., Ltd. C03-PF02-LP-MI07-SS(V01)

EAC30-DR-B-AL9

STUDY REFERENCE: C03-PF02-LP-MI07(V01)

IN VIVO EVALUATION AND COMPARISON OF THE EFFICACIES OF TWO WHITENING PRODUCTS BY CHROMAMETRY: A DOUBLE-BLIND PLACEBO-CONTROLLED SPLIT-FACE STUDY

NATURE OF THE TESTED PRODUCTS AND METHODS:

References of the products: Active: W1 Placebo: W4

Choice of the study: Randomized double-blind study; comparative test; each subject was her own control Kinetics: T0, T+1 month, T+2 months Application of the products: Each product was applied on one randomized half-face twice daily over a 2 month-

period, by the subjects themselves. Population: 21 subjects assessable at T0, 20 subjects at T+1 month and T+2 months Main criteria of inclusion: Healthy Asian female subjects, 18-65 years old, not having used whitening/anti-dark

spots products or any treatments (medicinal, hormonal, dermatological) in the past 6 weeks

TECHNIQUE: Chromametry (chromameter CR-300®, Minolta, Japan)

RESULTS AND CONCLUSION:

In our experimental conditions, we have demonstrated:

A significant lightening of the skin after 1 month of twice daily use of the test product W1 as demonstrated by the significant increases in the Luminance (+1.1%; p<0.01) and in the Individual Typological Angle (+7.7%; p<0.01) of the treated skin;

A slight and non significant darkening of the skin after 1 month of use of the placebo W4;

That the lightening observed for the skin treated with the test product W1 was significantly superior to the

effect observed for the skin treated with the placebo W4, after 1 month of utilization of the products.

A significant lightening of the skin after 2 months of twice daily use of the test product W1 as demonstrated by the significant increases in the Luminance (+1.7%; p<0.01) and in the Individual Typological Angle (+13.7%; p<0.01) of the treated skin;

A significant lightening of the skin after 2 months of twice daily use of the placebo W4 as demonstrated by

the significant increase in the Individual Typological Angle (+3.5%; p<0.05) of the treated skin, associated with the non significant increase in the Luminance L* (+0.4%);

That the lightening observed for the skin treated with the test product W1 was significantly superior to the

effect observed for the skin treated with the placebo W4, after 2 months of utilization of the products.

That the two tested products W1 and W4, applied twice daily during 2 months, were perfectly well tolerated by the subjects.

Date of handling of the study report

Study Manager Ms. P. PUNGPOD

Quality Assurance Mrs. C. PERRIER

Investigator Mr. F. PERIN

October 17, 2007

in vivo evaluation and comparison of the efficacies of … · the utilization of any other...

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