Clinical trial NCT02977507
Conditions: Melasma
Sponsor: Allergan
Start date: 2016-12-13; Completion date: 2017-10-09
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy and tolerability of Lytera 2.0 versus 4% hydroquinone in the improvement of the appearance of moderate facial melasma.

Detailed description:

Arms: arm 1: Lytera 2.0 applied to the affected areas (dark patches) on one side of the face twice a day, in the morning and evening, every day for 12 weeks. SkinMedica Facial Cleanser, SkinMedica Rejuvenative Moisturizer, and SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 Sunscreen were also applied to the face as directed. arm 2: 4% hydroquinone topical prescription cream applied to the affected areas (dark patches) on the other side of the face twice a day, in the morning and evening, every day for 12 weeks. SkinMedica Facial Cleanser, SkinMedica Rejuvenative Moisturizer, and SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 Sunscreen were also applied to the face as directed.
Interventions: intervention 1: Lytera 2.0 intervention 2: 4% Hydroquinone Topical Cream intervention 3: SkinMedica Facial Cleanser intervention 4: SkinMedica Rejuvenative Moisturizer intervention 5: SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 Sunscreen
Intervention descriptions: intervention 1: Lytera 2.0 applied to the affected areas twice a day, in the morning and evening, every day for 12 weeks. intervention 2: 4% Hydroquinone Topical Cream applied to the affected areas twice a day, in the morning and evening, every day for 12 weeks. intervention 3: SkinMedica facial cleanser applied to the face as directed. intervention 4: SkinMedica rejuvenative moisturizer applied to the face as directed. intervention 5: SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 sunscreen applied to the face as directed.

Protocol documents:
Prot_SAP_000.pdf: 
NCT02977507 
 
Study ID: SKM16‐LYT‐MEL 
 
Title:  Randomized, Double‐blinded, Split‐face Study comparing the Cosmetic Efficacy and Tolerability 
of Two Topical Products in Subjects with Moderate Facial Melasma 
 
 
Protocol Amendment 1 Date: 26 Oct 2016 


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Version Date: 26Oct16 
 
Randomized, Double-blinded, Split-face Study comparing the 
Cosmetic Efficacy and Tolerability of Two Topical Products 
in Subjects with Moderate Facial Melasma 
 
PROTOCOL NUMBER:  SKM16-LYT-MEL Amendment 1 
 
 
FUNDING SPONSOR: 
 
SkinMedica Inc., an Allergan Company 
2525 Dupont Drive  
Irvine, CA 92612 
 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
           
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL DATE: 
 
26/Oct/2016 
 
 
 
The study will be conducted according to the protocol and in compliance with 
International Conference of Harmonisation Good Clinical Practice Guidelines and all 
other applicable regulatory requirements. 
 
CONFIDENTIALITY STATEMENT 
THE INFORMATION PROVIDED IN THIS STUDY PROTOCOL IS INTENDED FOR 
REVIEW BY THE PRINCIPAL INVESTIGATOR, ALL RESEARCH RELATED 
PERSONNEL, 
ETHICS 
COMMITTEE(S) 
AND 
HEALTH 
AUTHORITIES. 
INFORMATION PROVIDED AND CAPTURED IN THIS PROTOCOL IS STRICTLY 
CONFIDENTIAL AND WILL ONLY BE DISCLOSED WITH WRITTEN CONSENT 
FROM THE SPONSORS. 


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Version Date: 26Oct16 
PROTOCOL SIGNATURE PAGE 
 
Randomized, Double-blinded, Split-face Study comparing the 
Cosmetic Efficacy and Tolerability of Two Topical Products 
in Subjects with Moderate Facial Melasma 
 
PROTOCOL NUMBER:  SKM16-LYT-MEL Amendment 1 
 
 
FUNDING SPONSOR: 
 
Skinmedica, Inc., An Allergan Company 
2525 Dupont Drive 
Irvine, CA 92612 
 
 
PRINCIPAL INVESTIGATOR:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL DATE: 
 
26/Oct/2016 
 
 
I, 
 agree to conduct protocol “Randomized, Investigator-
blinded, Split-face Study comparing the Cosmetic Efficacy and Tolerability of Two 
Topical Products in Subjects with Moderate Facial Melasma” in accordance and 
compliance with International Conference of Harmonisation Good Clinical Practice 
Guidelines and all applicable regulatory requirements. 
 
 
 
ACCEPTED AND AGREED: 
 
 
 
Principal Investigator Signature:
 
 
 
 


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Version Date: 26Oct16 
Table of Contents 
STUDY SYNOPSIS ............................................................................................................................... 5 
1.0  BACKGROUND .............................................................................................................................. 5 
2.0  STUDY OBJECTIVE ...................................................................................................................... 6 
3.0  STUDY POPULATION .................................................................................................................. 6 
3.1 Inclusion Criteria .......................................................................................................................... 6 
3.2 Exclusion Criteria ......................................................................................................................... 7 
4.0  METHODS AND MATERIALS ...................................................................................................... 9 
4.1 Study Products ............................................................................................................................. 9 
4.2 Subject Compliance .................................................................................................................. 10 
4.3 Concomitant Medications ......................................................................................................... 10 
4.4 Treatment Group Randomization ............................................................................................ 10 
 
 
 
6.0 ASSESSMENTS ............................................................................................................................ 13 
6.1 Clinical Grading of Efficacy Parameters ................................................................................ 13 
6.2 Investigator’s Tolerability Assessment ................................................................................... 15 
6.3 Subject MELASQOL Assessment ........................................................................................... 16 
6.4 Subject Self-Assessment Questionnaires .............................................................................. 16 
6.5 Imaging Procedures .................................................................................................................. 16 
6.6 
Mexameter Instrumentation Procedures .......................................................................... 16 
7.0  STATISTICS .................................................................................................................................. 17 
8.0 RESPONSIBILITIES OF THE INVESTIGATOR ....................................................................... 17 
8.1 Adherence to the Study Protocol ............................................................................................ 17 
8.2 Data Handling and Record Keeping ....................................................................................... 17 
9.0 REGULATORY OBLIGATIONS .................................................................................................. 17 
9.1 Institutional Review Board ........................................................................................................ 17 
9.2 Protocol ....................................................................................................................................... 18 
9.3 Informed Consent ...................................................................................................................... 18 
9.4 Protocol and Informed Consent Changes .............................................................................. 18 


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9.5 Study Monitoring ........................................................................................................................ 18 
10.0 CONFIDENTIALITY OF RECORDS ........................................................................................ 19 
11.0 DELEGATION OF INVESTIGATOR RESPONSIBILITIES ................................................... 19 
12.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................................ 19 
13.0 ADVERSE EVENTS AND REPORTING ................................................................................. 19 
13.1 Serious And/Or Adverse Event Reporting ........................................................................... 19 
13.2 Pregnancy During The Study ................................................................................................ 21 
13.3 Anticipated Reactions ............................................................................................................. 21 
13.4 Unknown/Unforeseeable Risks ............................................................................................. 21 
13.5 Unblinding ................................................................................................................................. 22 
14.0 
REFERENCES ......................................................................................................................... 22 
 
 
 
 
 
 


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Version Date: 26Oct16 
STUDY SYNOPSIS 
 
Protocol Number 
 
SKM16-LYT-MEL Amendment 1 
Protocol Title 
Randomized, Double-blinded, Split-face Study comparing the 
Cosmetic Efficacy and Tolerability of Two Topical Products in 
Subjects with Moderate Facial Melasma
Study Duration 
3 months (12 Weeks)
Study Population 
20 healthy subjects with Fitzpatrick Skin Types III-VI 
Objectives 
To evaluate and compare the efficacy and tolerability of two 
topical products in the improvement of facial melasma  
Study Design 
Single site, investigator-initiated, double-blinded, parallel arm, 
randomized treatment, split-face, 12-week study comparing the 
efficacy and tolerability of SkinMedica’s cosmetic topical 
brightener versus generic hydroquinone 4% topical prescription 
cream. A total of 20 healthy subjects will be enrolled into this 
study. Subjects will be screened and randomized at Baseline and 
will return for visits at Weeks 4, 8 and 12. The test products will 
be applied only to the affected areas (dark patches) twice a day, 
morning and evening, every day for 12 weeks. Ancillary products 
will be provided for basic daily skincare regimen use. 
Study Products 
 SkinMedica Facial Cleanser 
 SkinMedica Rejuvenative Moisturizer 
 SkinMedica Essential Defense Mineral Shield Broad 
Spectrum SPF 35 Sunscreen 
 Test Product A (Lytera 2.0) 
 Test Product B (4% Hydroquinone Topical Cream) 
Eligibility Criteria 
Subjects aged 18+ 
 
with symmetrical moderate facial melasma. 
 
 
1.0  BACKGROUND 
 
Melasma is a common disorder of hyperpigmentation which typically presents as brown 
or grayish brown macules on the face, including the forehead, malar region, upper lip 
and chin. Melasma is commonly observed in women with Fitzpatrick skin types III to V 
(1), especially Asian and Hispanic women, although all skin types can be affected.   
 
Contributing causes of melasma may include ultraviolet irradiation, oral contraceptives, 
hormone replacement therapy, pregnancy, and thyroid dysfunction (2) however the 
exact etiology are not yet fully understood. 
 


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Many patients find the uneven skin tone appearance caused by melasma to be 
cosmetically unacceptable.  Finding a successful treatment remains challenging and 
frustrating. Therapies include broad-spectrum sunscreens, hydroquinone, tretinoin, kojic 
acid, alpha hydroxy acids, salicylic acid, and chemical peels.  
 
The treatment of hyperpigmentation associated with skin aging and melasma is 
challenging due to the prolonged time to respond and its high relapse rate when therapy 
is discontinued.  Patients are also required to avoid sunlight to improve therapeutic 
results. Hydroquinone is currently the gold standard for the topical treatment of 
hyperpigmentation and melasma. 
 
2.0  STUDY OBJECTIVE 
 
The objective of this study is to evaluate the efficacy and tolerability of SkinMedica’s 
cosmetic topical brightener versus 4% hydroquinone in the improvement of the 
appearance of moderate facial melasma over the course of 12 weeks. 
 
3.0  STUDY POPULATION 
 
Twenty (20) healthy subjects presenting with symmetrical moderate facial melasma, 
who meet all inclusion and exclusion criteria will be eligible to participate in this study. 
 
3.1 Inclusion Criteria 
A subject will be eligible to participate if they meet all of the following inclusion 
criteria: 
 
1. Female or male aged 18+ years 
 
 
 
2. Individuals with symmetrical (with at least left and right malar region involvement) 
moderate melasma 
 
. 
 
3. Individuals that are willing to provide written informed consent and are able to 
read, speak, write, and understand English.  
 
4. Individuals willing to sign a photography release. 
 
5. Willing to withhold all facial treatments during the course of the study including 
botulinum toxin, injectable fillers, microdermabrasion, IPL, peels, facials, waxing, 
laser treatments and tightening treatments.  Threading is allowed but not facial 
laser hair removal. 
 


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6. Willingness to cooperate and participate by following study requirements  for the 
duration of the study and to report any changes in health status or medications, 
adverse event symptoms, or reactions immediately. 
 
7. Willingness to not begin using any new cosmetic facial make-up during the study. 
If regular users of cosmetic facial make-up, they must have used the product(s) 
without any tolerability issues for at least 2 weeks prior to starting the study. 
 
8. Willingness to avoid as much as possible, direct and prolonged sun exposure for 
the duration of the study (including tanning beds), especially from 10 AM to 2 
PM. Subjects are asked to wear protective clothing prior to and during exposure.  
Any extended sun exposure must be recorded in the source documents. 
 
3.2 Exclusion Criteria 
A subject will not be eligible to participate if they meet any of the following 
exclusion criteria. 
 
1. Individuals diagnosed with known allergies to study provided skin care products. 
 
2. Individuals who are nursing, pregnant, or planning to become pregnant during 
the study according to subject self-report. 
 
3. Individuals with a history of skin cancer. 
 
4. Individuals having a health condition and/or pre-existing or dormant dermatologic 
disease on the face (e.g., psoriasis, rosacea, acne, eczema, seborrheic 
dermatitis, severe excoriations etc.) that the Investigator or designee deems 
inappropriate for participation or could interfere with the outcome of the study. 
 
5. Individuals with a history of immunosuppression/immune deficiency disorders 
(including (HIV infection or AIDS) or currently using immunosuppressive 
medications (e.g., azathioprine, belimumab, cyclophosphamide, Enbrel, Imuran, 
Humira, mycophenolate mofetil, methotrexate, prednisone, Remicade, Stelara.) 
and/or radiation as determined by study documentation that the Investigator or 
designee deems inappropriate for participation or could interfere with the 
outcome of the study. 
 
6. Individuals with an uncontrolled disease such as asthma, diabetes, hypertension, 
hyperthyroidism, or hypothyroidism. Individuals having multiple health conditions 
may be excluded from participation even if   the conditions are controlled by diet, 
medication, etc. 
 
7. Individuals with any planned surgeries and/or invasive medical procedures during 
the course of the study. 
 


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8. Individuals who are currently participating in any other facial usage study or have 
participated in any clinical trial within 4 weeks prior to inclusion into the study. 
 
9. Individuals who have observable suntan, scars, nevi, excessive hair, etc. or other 
dermal conditions on the face that might influence the test results in the opinion 
of the Investigator or designee. 
 
10. Individuals who started hormone replacement therapies (HRT) or hormones for 
birth control less than 3 months prior to study entry or who plan on starting, 
stopping, or changing doses of HRT or hormones for birth control during the 
study. 
 
11. Individuals who used any of the following medications or had any of the listed 
procedures within the listed time frame prior to the study start date: 
 Retin-A®, Retin-A Micro®, Renova®, Avita®, Tazorac®, or Differin® 
within 3 months 
 Had a light-depth chemical peel or microdermabrasion within 1 month 
 Had a medium-depth chemical peel, medium-depth microdermabrasion, 
any systemic steroids, non-ablative laser, light and/or radio frequency or 
fractional laser resurfacing of the face and neck within 3 months 
 Any systemic retinoid (e.g. Soriatane®, Accutane®, Roche Dermatologics) 
within 12 months   
 Any topical or systemic antibiotics, such as minocycline, or any other 
known medications that can cause photosensitivity, such as 
hydrochlorothiazide, lasix, amiodarone, within 1 month 
 Any topical tretinoin product or derivative, imiquimod, 5-fluorouracil, or 
diclofenac on their face within 3 months 
 Prescription strength skin lightening products (e.g. 4% hydroquinone, 
tretinoin, AHA, BHA and polyhydroxy acids, 15% or 20% azelaic acid, 4-
hydroxyanisole alone or in combination with tretinoin, etc.) within 3 months 
 Any non-prescription cosmetic anti-wrinkle, skin lightening products, or 
any other product or topical or systemic medication known to affect skin 
aging or dyshcromia (products containing alpha/beta/poly-hydroxy acids, 
vitamin C, soy, Q-10, hydroquinone; systemic or licorice extract (topically), 
Tego® Cosmo C250, gigawhite, lemon juice extract (topically), emblica 
extract, etc.) within 2 weeks 
 Have undergone plastic surgery, Dermabrasion (deep skin peel), a deep 
chemical peel or ablative laser resurfacing of the face and neck within 12 
months 
 Had facial treatment with a botulinum toxin base injectable (Botox), 
injectable fillers, or a fat transfer within 6 months 
 
 
 


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SkinMedica Facial Cleanser: Water/Aqua/Eau,Disodium Laureth 
Sulfosuccinate,Cocamidopropyl Hydroxysultaine,Sodium Lauryl 
Sulfoacetate,Camellia Oleifera Leaf Extract, Glycerin, Panthenol, Butylene 
Glycol, Ethylhexylglycerin,PEG-150 Pentaerythrityl Tetrastearate, PEG-6, 
Caprylic/Capric, Glycerides, Disodium EDTA, Phenoxyethanol, 
Parfum/Fragrance, Blue 1 (CI 42090), Yellow 10 (CI 47005) 
 
Test Product A (Cosmetic topical serum “Lytera 2.0”): Water/Aqua/Eau, Butylene 
Glycol, Glycerin, Niacinamide, Polyacrylate-13,  Phenylethyl Resorcinol, 
Tranexamic Acid, Vitis Vinifera (Grape) Flower Cell Extract, Plankton Extract, 
Tetrapeptide-30, Artemisia Capillaris Flower Extract, Vibrio Alginolyticus Ferment 
Filtrate, Alteromonas Ferment Extract, Tocopheryl Acetate, Polyisobutene, 
Polysorbate 20, Caprylic/Capric Triglyceride, Hydroxyacetophenone, Phytic Acid, 
Diethylhexyl Syringylidenemalonate, Disodium EDTA, Ethylhexylglycerin, 
Phenoxyethanol  
 
SkinMedica Rejuvenative Moisturizer: Water/Aqua/Eau, Caprylic/Capric 
Triglyceride, Tocopheryl Acetate, Diglycerin, Isostearyl Behenate, Glyceryl 
Stearate, PEG-100 Stearate, Tetrahexyldecyl Ascorbate, Butyrospermum Parkii 
Butter, Panthenol, Phytosterols, Tocopherol, Tocotrienols, Squalene, Oryza 
Sativa Bran Cera, Aloe Barbadensis Leaf Juice, Algae Extract, Bisabolol, Ginkgo 
Biloba Leaf Extract, Avena Sativa Kernel Extract, Sodium Hyaluronate, Stearyl 
Glycyrrhetinate, Retinyl Palmitate, Glycerin, Glyceryl Polyacrylate, Dimethicone, 
Cetyl Alcohol, Cetearyl Alcohol, Ceteareth-20, Caprylyl Methicone, Carbomer, 
Tromethamine, Disodium EDTA , Potassium Sorbate, Phenoxyethanol, 
Ethylhexylglycerin, Parfum/Fragrance 
 
 
SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 
Sunscreen: Water, Cyclopentasiloxane, Dimethicone, Polyglyceryl-3 
Polydimethylsiloxyethyl Dimethicone, Butylene Glycol, Aluminum Hydroxide, 
Dimethicone/PEG-10/15 Crosspolymer, PEG-9 Polydimethylsiloxyethyl 
Dimethicone, Sodium Chloride, Caffeine, Camellia oleifera Leaf Extract, Sodium 
Citrate, Dimethicone/Vinyl Dimethicone Crosspolymer, Triethoxysilylethyl 
Polydimethylsiloxyethyl Hexyl Dimethicone, Stearic Acid, Ethylhexylglycerin, 
Phenoxyethanol 
 
Test Product B (4% Hydroquinone Topical Prescription Cream): 
 
[Ingredients TBD depending on Pharmacy] 
(
y
q
p
[Ingredients TBD depending on Pharmacy]


Protocol: SKM16-LYT-MEL 
                    
      Sponsor: SkinMedica, Inc.  
 
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Version Date: 26Oct16 
4.2 Subject Compliance 
Subject compliance to the study treatment regimen will be verbally assessed; 
study personnel will ask each subject whether they missed any applications of 
study treatment since the previous visit and will quantify the subject’s response. 
 
4.3 Concomitant Medications 
Systemic and topical medications being used at baseline that are considered 
necessary for the subject’s welfare and will not interfere with the study may be 
used.  Administration of these drugs must be reported on the appropriate case 
report form and any alterations in the use of the medication during the study will 
be carefully noted.  Administration of a prohibited drug (see section 4.2 of 
protocol) in an emergency situation is done with the safety of the study 
participant as the prime consideration.  All topical and systemic medications that 
the subject receives during the study will be recorded.  Any alterations will be 
noted. 
 
 
4.4 Treatment Group Randomization 
Subjects will be randomized in a 1:1 fashion to receive treatment with 
SkinMedica’s cosmetic topical brightener or 4% hydroquinone. A randomization 
table will be provided by the sponsor and used to determine which facial side will 
be treated with Test Product A (cosmetic topical serum “Lytera 2.0”) and Test 
Product B (4% hydroquinone) for each subject.  


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Version Date: 26Oct16 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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 Randomization and distribution of study products by the Unblinded study staff 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  


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. 
 
Version Date: 26Oct16 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
6.0 ASSESSMENTS  
 
6.1 Clinical Grading of Efficacy Parameters 
 
Clinical grading of the efficacy parameter will be performed at the study visits indicated. 
Hyperpigmentation will be assessed on the left and the right side of each subject’s 
face separately. 
 
Melasma Severity Rating Scale: 
At the screening/baseline visit and the end of treatment visit (week 12), the 
Invesgator will assess the subject’s facial skin for the severity of symmetrical 
facial melasma using the following Melasma Severity Rating Scale on the left and 
right facial sides. Subjects must present with a score of 2 for the left and the right 
facial sides to be enrolled into the study. 
Score 
Hyperpigmentation Status
0 
Cleared: color of melasma lesions 
approximately equivalent to 
surrounding normal skin or with 
minimal residual hyperpigmentation
1 
Mild: color slightly darker than the 
surrounding normal skin
2 
Moderate: color moderately darker 
than the surrounding normal skin
3 
Severe: color markedly darker than 
the surrounding normal skin
 


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Version Date: 26Oct16 
Overall Hyperpigmentation Scale: 
At all visits (baseline, weeks 4, 8 and 12), the Investigator will globally assess the 
subject’s left and right facial sides for overall hyperpigmentation using the 
following ten point scale (0 – 9): 
None 
(Score of 0) 
 
Skin is normal in color with no evidence of 
hyperpigmentation 
 
Mild  
(Score of 1, 2 or 3) 
Several brown spots with increased pigmentation; they are 
small in size and slightly darker than surrounding skin 
Moderate 
(Score of 4, 5 or 6) 
Many brown spots with increased pigmentation; they are 
medium in size and much darker than surrounding skin 
Severe 
(Score of 7, 8 or 9) 
Many large brown spots with increased pigmentation; they 
are large in size and markedly darker than surrounding skin
 
 
Half-face Evaluation of Melasma Area Severity Index (MASI) Score 
At all visits, (baseline, weeks 4, 8 and 12), the Investigator will assign a grade for 
the left and right facial sides, for each of the below units, for the variable A 
(percentage of each area involved), D (darkness of pigment) and P (pattern of 
involvement), as described in detail below.   
Calculations will be conducted by the sponsor upon receipt of the completed 
CRFs. 
3 variables are assessed for each half- facial unit: 
- 
Total Area Involved (A) 
- 
Darkness of pigment (D)  
- 
Homogeneity (H) 
 
Variable Definitions: 
A = A numerical value is assigned for the corresponding percentage of the 
total area of the facial segment being assessed.  
This value represents ONLY the percent of the area involved, not the pattern or 
darkness of the pigment. 
0=  No involvement 
1= <10% involvement 
2= 10-29% involvement 
3= 30-49% involvement 
4= 50-69% involvement 
5= 70-89% involvement 
6= 90-100% involvement  
 


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D = Darkness of the pigment compared to adjacent normal pigment.  
0= Normal skin color  
1= Slightly darker than normal color 
2 = Mild hyperpigmentation 
3= Modrate hyperpigmentation,clearly and distinctly darker than normal 
pigment 
4 = Severe hyperpigmentation,virtually black pigment  
 
H = The homogeneity of the pigmentation will be assessed using the below 
scale: 
0= Normal skin color without evidence of hyperpigmentation 
1= Specks of involvement  
2 = Small patchy areas of involvement < 1.5 cm diameter  
3 = Patches of involvement> 2 cm diameter  
4 = Uniform skin involvement without any clear areas  
 
Calculation of the half-face MASI score:  
To calculate the half-face MASI score, the sum of the severity grade for darkness 
(D) and homogeneity (H) is multiplied by the numerical value of the areas (A) 
involved and by the percentages of the four facial areas (10-30%). 
 
Total Half-Face MASI score:  
Half Forehead 0.15(D+H)A + One Malar Side 0.3 (D+H)A + Half Chin 
0.05(D+H)A 
 
 
Investigator’s Global Improvement Assessment- Overall 
Hyperpigmentation: 
 
The expert grader will also score an Investigator’s Global Improvement 
Assessment for Overall Hyperpigmentation on the left and right facial sides at all 
follow-up visits (weeks 4, 8, and 12). 
0=No change or worsening 
1=Mild improvement (~25% overall improvement) 
2=Moderate improvement (~50% overall improvement) 
3=Marked improvement (~75% overall improvement) 
4=Complete clearing/Dramatic improvement (~95%+ overall improvement) 
 
6.2 Investigator’s Tolerability Assessment 
Tolerability of the test products will be assessed through the capture of adverse events 
reported throughout the study period. Any adverse event(s) experienced by the subject 


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Version Date: 26Oct16 
during the study period, whether related to the treatment or not, will be recorded in the 
“Case Report Form.” 
6.3 Subject MELASQOL Assessment  
Subjects will complete the MELASQOL assessement regarding their full face at the 
baseline visit and their left and right facial sides at week 12. The MELASQOL is a 
validated assessment to help measure the emotional and psychological impact of 
melasma (3).  This questionnaire is found in 
  
 
6.4 Subject Self-Assessment Questionnaires  
Subjects will complete a Sponsor-provided self-assessment questionnaire at follow-up 
visits at weeks 4, 8, and 12. The assessment consists in a personal and subjective 
evaluation of their facial skin quality on the left and right side during and after the 
treatment by the subject. In addition, the assessment serves to evaluate the self-
perceived cosmetic efficacy of the treatment and the product attributes. This 
questionnaire is found in 
 
 
6.5 Imaging Procedures 
Photographs will be taken at all visits utilizing standardized conditions for all subjects.  
The skin must be cleansed prior to photography to remove any makeup, including 
foundation makeup, lipstick/gloss and eye shadow. The settings for the exposure, 
lighting, flash, and focal length will be maintained constant over the course of the study.  
 
Ensure that subjects jewelry is removed from ears/neck and hair is pushed back away 
from the face, ensuring that no stray hairs are in the facial area. 
Subjects will be photographed using an appropriate clinical digital photography system 
 at highest resolution in a 
consistent position. Importantly, the photography should be taken to enable comparison 
of baseline photos with later photos taken at the end of the treatment period. For 
instance, if available, the overlay function must be used. As each photograph is being 
taken, it should be viewed to ensure that it is in focus and is similar to its baseline 
counterpart in all technical aspects, including lighting, distance and angle. In addition, 
the face should be captured in neutral facial expressions and neutral angles (e.g., 
avoiding hypo- or hyperextension of the neck).  
 
Photos using the 
 will be taken from three angles to enable the improvement to 
be clearly noticed: full frontal (0°) and at profile from the left (45°) and from the right side 
(45°). Photos will be taken at controlled distances under standard room lighting. Cross-
polarized, parallel- polarized and visible light images will be acquired along with both 
blue fluorescence and ultraviolet fluorescence images. During the photography, the 
subjects will be asked to keep their eyes closed. 
 
6.6 Mexameter Instrumentation Procedures 
Two target hyperpigmented lesions will be selected from the left (1) and the right (2) 
malar facial areas and measured by the mexameter, and instrument that measures 


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Version Date: 26Oct16 
melanin content. Measurements at subsequent visits must be taken from the same 
target lesion locations as at the baseline visit within each subject. 
One target “normal” measurement will also be taken from an unaffected skin area on 
the face representing normal skin. The values from the target hyperpigmented lesions 
will be compared to the normal lesion value. 
 
7.0  STATISTICS 
Statistical analyses will be conducted by the sponsor on an intent-to-treat basis (ex: all 
enrolled subjects, with at least one follow-up visit, will be included in the analysis).   
 
8.0 RESPONSIBILITIES OF THE INVESTIGATOR 
8.1 Adherence to the Study Protocol 
The Investigator must ensure adherence to the procedures outlined in this Study 
Protocol.  The procedures set out in this study protocol, pertaining to the conduct, 
evaluation, and documentation of this study, are designed to ensure that the 
Investigator abides by GCP as described in the ICH Guidelines Topic E6: 
“Guideline for Good Clinical Practice.”  Compliance with these regulations also 
constitutes compliance with the ethical principles described in the current revision 
of the Declaration of Helsinki.  The study will also be carried out in keeping with 
local legal and regulatory requirements. 
 
8.2 Data Handling and Record Keeping 
The Investigator must ensure that proper source documentation for all study 
activities are diligently maintained and securely kept.  The Investigator will 
transfer all relevant data to the Case Report Form as stipulated in this Study 
Protocol and his/her signature on the Case Report Form guarantees 
completeness and integrity of these data.  The Investigator will store all study 
related supplies in a secure and locked location. In addition, the Investigator will 
ensure that all Case Report Forms will be maintained for a period of two years 
after the conclusion of the study. 
 
9.0 REGULATORY OBLIGATIONS 
9.1 Institutional Review Board 
The study protocol, informed consent forms (all versions), and any specific 
advertising will be submitted to and approved by Independent Investigational 
Review Board before the start of the study.  A form must be signed by the 
chairman or designee of the IRB noting the approvals. This notification will be 
provided to SkinMedica for notification of study initiation. 


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9.2 Protocol 
The Investigator signing the protocol signature page will act as the Principal 
Investigator at this site. Protocols will be noted as approved by the Investigator 
by placement of his signature on the Investigator’s Signature Page.  Copies of 
the IRB approved protocol and informed consents will be provided to 
SkinMedica. 
 
9.3 Informed Consent 
An Informed Consent Form (ICF) that includes all of the relevant elements 
currently required by FDA or state regulations will be provided to each 
prospective study subject at screening and before enrollment into the study.  The 
type and method of study, any potential or possible hazards, and the subject’s 
right to withdraw from the study at any time will be explained to the subjects by 
the Investigator or Designee. Once the Investigator or Designee is assured that 
an individual candidate understands the implications of participating in this study, 
the subject will be asked to give consent by signing and dating in the appropriate 
areas of the Informed Consent Form.  The Investigator or Designee will also sign 
and date the ICF.  A copy of the IRB approved ICF will be given to the subject for 
the subject’s records and the original will be filed in the subject’s binder or folder. 
 
9.4 Protocol and Informed Consent Changes 
Changes to the protocol or Informed Consent Forms will be implemented as 
amendments to the original document and approved by the IRB.  The approvals 
will be processed in accordance with the established IRB procedures.  Copies of 
all protocol and ICF amendments/revisions, along with letters noting IRB 
approval, will be submitted to SkinMedica, as this may affect safety.  Any 
addenda, amendment or revision that substantially alters the study design or 
increases potential risk to the subject will require the subject’s consent to 
continue in the study. 
 
9.5 Study Monitoring 
The site will be responsible for internal verification of complete and accurate data 
collection and confirming adherence to the protocol throughout the study. The 
study may be monitored by Sponsor representatives to ensure that the protocol 
and GCP guidelines are being followed and to assist in resolving any difficulties 
encountered while the study is in progress. The monitoring may include site visits 
and frequent communications (telephone, fax, email, letters). 
 


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10.0 CONFIDENTIALITY OF RECORDS 
 
Information about the subject’s health taken during this study may be used and given to 
others by the study coordinators, the medical staff, the respective study center and by 
the subject’s doctors and their other healthcare providers. The subject’s doctors and 
their healthcare providers may share health information about the subject with the 
investigator and study coordinator. The study coordinator and the providers may share 
that information with researchers participating in this study’s laboratories conducting 
tests for this study. A final study report may be shared with SkinMedica, Inc.; The U.S. 
Food and Drug Administration (FDA); Department of Health and Human Services 
(DHHS) agencies; other U.S. and foreign government agencies that watch over quality, 
safety and effectiveness of research. 
 
All research related personnel will ensure subject confidentiality is maintained. All 
subject related documents will be identified by subject initials and subject identification 
numbers. All subject related documents will be filed in individual subject binders or 
folders and stored in confidence by the site only to be accessed by research related 
personnel. 
 
11.0 DELEGATION OF INVESTIGATOR RESPONSIBILITIES 
 
The Investigator should ensure that all persons assisting with the trial are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and 
their trial-related duties and functions.  The investigator should maintain a list of sub-
investigators and other appropriately qualified persons to whom he has delegated 
significant trial-related duties. 
 
12.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The Investigator must ensure that institutional regulations, the Informed Consent Form, 
and the HIPAA Authorization clearly permit study-related monitoring, audits, IRB review, 
and regulatory inspections providing direct access to source data and documents. 
 
13.0 ADVERSE EVENTS AND REPORTING 
 
13.1 Serious And/Or Adverse Event Reporting 
A serious adverse event is any untoward medical occurrence, that, at any dose: 
 results in death; 
 is life-threatening; 


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 requires in-subject hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity;  
 is a congenital anomaly/birth defect; or 
 is an important medical event. 
 
Throughout the study, subjects will be monitored for signs and symptoms of 
adverse events.  An adverse event is any pathological or unintended change in 
the structure, function or chemistry of the body that occurs during the study, 
irrespective of causality, including any illness, injury, toxicity, sensitivity, or 
sudden death.  The condition must either not be present pre-study or must 
worsen in either intensity or frequency during the study. 
 
An unanticipated adverse study drug event is any drug-related adverse event, 
which is not identified in nature, severity, or frequency in current literature on the 
test article. 
 
All adverse events, including serious and study drug related or unanticipated 
adverse drug events, must be recorded and assessed by the Investigator.  In the 
event of an adverse event, serious adverse event or unanticipated adverse drug 
event, the physician will provide optimal subject care. 
 
Subjects who have had a serious adverse event must be followed clinically until 
all parameters, including laboratory values, have either returned to normal or are 
otherwise explained. 
 
Any serious adverse event or unanticipated adverse drug event occurring in this 
study will be analyzed and identified by the investigator and reported to the IRB 
within 10 business days, as per IND regulations and FDA Guidance. The 
investigator will also determine the event related to the study drug and report that 
event to the manufacture of the device, if necessary. 
 
Serious adverse events will be reported to the Sponsor within 24 hours (or the 
next working day). The main Sponsor contact for serious adverse events is: 
 
 
 
 
 
If death was the outcome of the event on the initial SAE Report, a Follow-
up/Final Report, including autopsy report, when performed, must be completed. 
 


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13.2 Pregnancy During The Study 
If a subject of childbearing potential becomes pregnant at any time while 
participating during the study, the pregnancy will be deemed an Adverse Event 
and the subject will stop all protocol related procedures. The investigator will 
follow-up with the subject until the pregnancy reaches term or until the pregnancy 
has been resolved. 
 
The Investigator will report the Adverse Event of pregnancy to the IRB within 24 
hours of awareness of the event and follow-up reports will be filed with the IRB 
as information with changes of the pregnancy becomes available. 
 
13.3 Anticipated Reactions 
All test materials have the potential to cause some minor side-effects or other 
reactions. Possible reactions to the test material(s) may include (but are not 
limited to) subjective sensations (such as itching, burning, stinging, tingling), 
scaling/dryness, and redness. Additionally, test material(s) applied to the eye 
areas have the potential to cause eye watering/tearing, redness of the eyes, 
corneal erosions, and foreign body sensation in the eyes.  
 
Symptoms of mild to moderate irritation, including the examples discussed 
above, will not be treated as adverse reactions if they are mild in nature. These 
conditions may or may not resolve over time. Symptoms that are persistent and 
moderate to severe in nature, or that involve elevation (e.g. edema, papules, 
vesicles, spreading) will be considered AEs.  
In rare cases, it is possible for a subject to develop allergic reactions to the test 
material(s). This risk is increased for individuals with a history of allergies, and 
individuals with asthma and/or a history of hives may also be affected. Subjects 
will be instructed to notify the clinic immediately if they experience an allergic 
reaction including rash, hives, and itching.  
The Investigator or designee will have the final authorization to determine if a 
reaction will be considered an AE.  
 
13.4 Unknown/Unforeseeable Risks 
In addition to the risks listed above, there may be some unknown or infrequent 
and unforeseeable risks associated with the use of the assigned study products. 
Subjects will be informed both verbally and in writing in a timely manner of any 
new information, findings or changes to the way the research will be performed 
that might influence their willingness to continue their participation in this study. 
 
Pregnancy/Fetal Risks:  The effects of SkinMedica Facial Cleanser, Rejuvenative 
Moisturizer, Essential Defense Mineral Shield Broad Spectrum SPF 35, Test 
Product A (Lytera 2.0) and Test Product B (4% Hydroquinone) have not been 
studied in pregnancy and therefore may be hazardous.   
 


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If a subject thinks that she may be pregnant or have become pregnant during the 
study she is to inform the study doctor immediately. If a subject becomes 
pregnant or thinks they may be pregnant, they will be removed from the study 
and the study doctor will refer the subject to seek obstetric care and may request 
to track their pregnancy and will report  to the IRB. 
 
13.5 Unblinding 
In the event that a subject experiences an Adverse Event or Serious Adverse 
Event, the Investigator and/or Sub-Investigator will become unblinded. 
 
14.0 REFERENCES 
1. Melasma: a clinical and epidemiological review* Ana Carolina Handel, Luciane 
Donida Bartoli Miot, and Hélio Amante Miot, An Bras Dermatol. 2014 Sep-Oct; 
89(5): 771–782. 
2. Melasma. Etiologic and Therapeutic Considerations, Pearl E. Grimes, MD, Arch 
Dermatol. 1995;131(12):1453-1457. 
3. Development and validation of a health-related quality of life instrument for 
women with melasma. R. Balkrishnan, et.al. Br J Dermatol. 2003;149:572-577. 
 
 


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Version Date: 10Aug16 
 
Randomized, Double-blinded, Split-face Study comparing the 
Cosmetic Efficacy and Tolerability of Two Topical Products 
in Subjects with Moderate Facial Melasma 
 
PROTOCOL NUMBER:  SKM16-LYT-MEL 
 
 
FUNDING SPONSOR: 
 
SkinMedica Inc., an Allergan Company 
2525 Dupont Drive  
Irvine, CA 92612 
 
 
 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
          
 
      
 
 
 
 
 
 
 
 
 
PROTOCOL DATE: 
10/Aug/2016 
 
 
 
 
The study will be conducted according to the protocol and in compliance with 
International Conference of Harmonisation Good Clinical Practice Guidelines and all 
other applicable regulatory requirements. 
 
CONFIDENTIALITY STATEMENT 
THE INFORMATION PROVIDED IN THIS STUDY PROTOCOL IS INTENDED FOR 
REVIEW BY THE PRINCIPAL INVESTIGATOR, ALL RESEARCH RELATED 
PERSONNEL, 
ETHICS 
COMMITTEE(S) 
AND 
HEALTH 
AUTHORITIES. 
INFORMATION PROVIDED AND CAPTURED IN THIS PROTOCOL IS STRICTLY 
CONFIDENTIAL AND WILL ONLY BE DISCLOSED WITH WRITTEN CONSENT 
FROM THE SPONSORS. 




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Version Date: 10Aug16 
Table of Contents 
STUDY SYNOPSIS ................................................................................................................... 5 
1.0  BACKGROUND .................................................................................................................. 5 
2.0  STUDY OBJECTIVE .......................................................................................................... 6 
3.0  STUDY POPULATION ....................................................................................................... 6 
3.1 Inclusion Criteria .............................................................................................................. 6 
3.2 Exclusion Criteria ............................................................................................................. 7 
4.0  METHODS AND MATERIALS ........................................................................................... 8 
4.2 Study Products ................................................................................................................ 9 
4.3 Subject Compliance ....................................................................................................... 10 
4.4 Concomitant Medications .............................................................................................. 10 
4.5 Treatment Group Randomization .................................................................................. 10 
 
6.0 ASSESSMENTS ............................................................................................................... 13 
6.1 Clinical Grading of Efficacy Parameters ........................................................................ 13 
6.2 Investigator’s Tolerability Assessment ........................................................................... 16 
6.3 Self-Assessment By Questionnaire ............................................................................... 16 
6.4 Imaging Procedures ....................................................................................................... 16 
7.0  STATISTICS ..................................................................................................................... 17 
8.0 RESPONSIBILITIES OF THE INVESTIGATOR ............................................................... 17 
8.1 Adherence to the Study Protocol ................................................................................... 17 
8.2 Data Handling and Record Keeping .............................................................................. 18 
9.0 REGULATORY OBLIGATIONS ........................................................................................ 18 
9.1 Institutional Review Board ............................................................................................. 18 
9.2 Protocol .......................................................................................................................... 18 
9.3 Informed Consent .......................................................................................................... 18 
9.4 Protocol and Informed Consent Changes ...................................................................... 19 
9.5 Study Monitoring ............................................................................................................ 19 
10.0 CONFIDENTIALITY OF RECORDS ............................................................................... 19 
11.0 DELEGATION OF INVESTIGATOR RESPONSIBILITIES.............................................. 20 


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. 
 
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12.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................. 20 
13.0 ADVERSE EVENTS AND REPORTING ......................................................................... 20 
13.1 Serious And/Or Adverse Event Reporting ................................................................... 20 
13.2 Pregnancy During The Study ....................................................................................... 21 
13.3 Anticipated Reactions .................................................................................................. 21 
13.4 Unknown/Unforeseeable Risks .................................................................................... 22 
13.5 Unblinding .................................................................................................................... 22 
14.0 REFERENCES ................................................................................................................ 22 
 
 
 
 
 
 


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Version Date: 10Aug16 
STUDY SYNOPSIS 
 
Protocol Number 
 
SKM16-LYT-MEL 
Protocol Title 
Randomized, Double-blinded, Split-face Study comparing the 
Cosmetic Efficacy and Tolerability of Two Topical Products in 
Subjects with Moderate Facial Melasma 
Study Duration 
3 months (12 Weeks) 
Study Population 
20 healthy subjects with Fitzpatrick Skin Types III-VI 
Objectives 
To evaluate and compare the efficacy and tolerability of two 
topical products in the improvement of facial melasma  
Study Design 
Single site, investigator-initiated, double-blinded, parallel arm, 
randomized treatment, split-face, 12-week study comparing the 
efficacy and tolerability of SkinMedica’s cosmetic topical 
brightener versus generic hydroquinone 4% topical prescription 
cream. A total of 20 healthy subjects will be enrolled into this 
study. Subjects will be screened and randomized at Baseline and 
will return for visits at Weeks 4, 8 and 12. The test products will 
be applied only to the affected areas (dark patches) twice a day, 
morning and evening, every day for 12 weeks. Ancillary products 
will be provided for basic daily skincare regimen use. 
Study Products 
 SkinMedica Facial Cleanser 
 SkinMedica Rejuvenative Moisturizer 
 SkinMedica Essential Defense Mineral Shield Broad 
Spectrum SPF 35 Sunscreen 
 Test Product A (Lytera 2.0) 
 Test Product B (4% Hydroquinone Topical Cream ) 
Eligibility Criteria 
Subjects aged 18+ with 
 
symmetrical moderate facial melasma.  
 
 
1.0  BACKGROUND 
 
Melasma is a common disorder of hyperpigmentation which typically presents as brown 
or grayish brown macules on the face, including the forehead, malar region, upper lip 
and chin. Melasma is commonly observed in women with Fitzpatrick skin types III to V 
(1), especially Asian and Hispanic women, although all skin types can be affected.   
 
Contributing causes of melasma may include ultraviolet irradiation, oral contraceptives, 
hormone replacement therapy, pregnancy, and thyroid dysfunction (2) however the 
exact etiology are not yet fully understood. 
 


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Many patients find the uneven skin tone appearance caused by melasma to be 
cosmetically unacceptable.  Finding a successful treatment remains challenging and 
frustrating. Therapies include broad-spectrum sunscreens, hydroquinone, tretinoin, kojic 
acid, alpha hydroxy acids, salicylic acid, and chemical peels.  
 
The treatment of hyperpigmentation associated with skin aging and melasma is 
challenging due to the prolonged time to respond and its high relapse rate when therapy 
is discontinued.  Patients are also required to avoid sunlight to improve therapeutic 
results. Hydroquinone is currently the gold standard for the topical treatment of 
hyperpigmentation and melasma. 
 
2.0  STUDY OBJECTIVE 
 
The objective of this study is to evaluate the efficacy and tolerability of SkinMedica’s 
cosmetic topical brightener versus 4% hydroquinone in the improvement of the 
appearance of moderate facial melasma over the course of 12 weeks. 
 
3.0  STUDY POPULATION 
 
Twenty (20) healthy subjects presenting with symmetrical moderate facial melasma, 
who meet all inclusion and exclusion criteria will be eligible to participate in this study. 
 
3.1 Inclusion Criteria 
A subject will be eligible to participate if they meet all of the following inclusion 
criteria: 
 
1. Female or male aged 18+ years 
 
 
 
2. Individuals with symmetrical (with at least left and right malar region involvement) 
moderate melasma 
 
 
 
3. Individuals that are willing to provide written informed consent and are able to 
read, speak, write, and understand English.  
 
4. Individuals willing to sign a photography release. 
 
5. Willing to withhold all facial treatments during the course of the study including 
botulinum toxin, injectable fillers, microdermabrasion, IPL, peels, facials, waxing, 
laser treatments and tightening treatments.  Threading is allowed but not facial 
laser hair removal. 
 


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6. Willingness to cooperate and participate by following study requirements  for the 
duration of the study and to report any changes in health status or medications, 
adverse event symptoms, or reactions immediately. 
 
7. Willingness to not begin using any new cosmetic facial make-up during the study. 
If regular users of cosmetic facial make-up, they must have used the product(s) 
without any tolerability issues for at least 2 weeks prior to starting the study. 
 
8. Willingness to avoid as much as possible, direct and prolonged sun exposure for 
the duration of the study (including tanning beds), especially from 10 AM to 2 
PM. Subjects are asked to wear protective clothing prior to and during exposure.  
Any extended sun exposure must be recorded in the source documents. 
 
3.2 Exclusion Criteria 
A subject will not be eligible to participate if they meet any of the following 
exclusion criteria. 
 
1. Individuals diagnosed with known allergies to study provided skin care products. 
 
2. Individuals who are nursing, pregnant, or planning to become pregnant during 
the study according to subject self-report. 
 
3. Individuals with a history of skin cancer. 
 
4. Individuals having a health condition and/or pre-existing or dormant dermatologic 
disease on the face (e.g., psoriasis, rosacea, acne, eczema, seborrheic 
dermatitis, severe excoriations etc.) that the Investigator or designee deems 
inappropriate for participation or could interfere with the outcome of the study. 
 
5. Individuals with a history of immunosuppression/immune deficiency disorders 
(including (HIV infection or AIDS) or currently using immunosuppressive 
medications (e.g., azathioprine, belimumab, cyclophosphamide, Enbrel, Imuran, 
Humira, mycophenolate mofetil, methotrexate, prednisone, Remicade, Stelara.) 
and/or radiation as determined by study documentation that the Investigator or 
designee deems inappropriate for participation or could interfere with the 
outcome of the study. 
 
6. Individuals with an uncontrolled disease such as asthma, diabetes, hypertension, 
hyperthyroidism, or hypothyroidism. Individuals having multiple health conditions 
may be excluded from participation even if   the conditions are controlled by diet, 
medication, etc. 
 
7. Individuals with any planned surgeries and/or invasive medical procedures during 
the course of the study. 
 


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8. Individuals who are currently participating in any other facial usage study or have 
participated in any clinical trial within 4 weeks prior to inclusion into the study. 
 
9. Individuals who have observable suntan, scars, nevi, excessive hair, etc. or other 
dermal conditions on the face that might influence the test results in the opinion 
of the Investigator or designee. 
 
10. Individuals who started hormone replacement therapies (HRT) or hormones for 
birth control less than 3 months prior to study entry or who plan on starting, 
stopping, or changing doses of HRT or hormones for birth control during the 
study. 
 
11. Individuals who used any of the following medications or had any of the listed 
procedures within the listed time frame prior to the study start date: 
 Retin-A®, Retin-A Micro®, Renova®, Avita®, Tazorac®, Soriatane®, or 
Differin® within 4 months 
 Had a chemical peel, dermabrasion, non-ablative laser or fractional laser 
resurfacing of the face and neck within 1 month. 
 Accutane® within 12 months   
 Prescription strength skin lightening products (e.g. hydroquinone, tretinoin, 
AHA, BHA and polyhydroxy acids, 4-hydroxyanisole alone or in 
combination with tretinoin, etc.) within 3 months 
 Any anti-wrinkle, skin lightening products, or any other product or topical 
or systemic medication known to affect skin aging or dyshcromia (products 
containing alpha/beta/poly-hydroxy acids, vitamin C, soy, Q-10, 
hydroquinone; systemic or licorice extract (topically), Tego® Cosmo C250, 
gigawhite, lemon juice extract (topically), emblica extract, etc.) within 2 
weeks. 
 Have undergone a regimen of Thermage treatments or an equivalent type 
of high energy treatments, plastic surgery, or ablative laser resurfacing of 
the face and neck within 12 months 
 Had facial treatment with a botulinum toxin base injectable (Botox), 
injectable fillers, or a fat transfer within 6 months. 
 
4.0  METHODS AND MATERIALS 
 
 
 
 
 
  
 
 


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4.2 Study Products 
 
SkinMedica Facial Cleanser: Water/Aqua/Eau,Disodium Laureth 
Sulfosuccinate,Cocamidopropyl Hydroxysultaine,Sodium Lauryl 
Sulfoacetate,Camellia Oleifera Leaf Extract, Glycerin, Panthenol, Butylene 
Glycol, Ethylhexylglycerin,PEG-150 Pentaerythrityl Tetrastearate, PEG-6, 
Caprylic/Capric, Glycerides, Disodium EDTA, Phenoxyethanol, 
Parfum/Fragrance, Blue 1 (CI 42090), Yellow 10 (CI 47005) 
 
Test Product A (Cosmetic topical serum “Lytera 2.0”): Water/Aqua/Eau, Butylene 
Glycol, Glycerin, Niacinamide, Polyacrylate-13,  Phenylethyl Resorcinol, 
Tranexamic Acid, Vitis Vinifera (Grape) Flower Cell Extract, Plankton Extract, 
Tetrapeptide-30, Artemisia Capillaris Flower Extract, Vibrio Alginolyticus Ferment 
Filtrate, Alteromonas Ferment Extract, Tocopheryl Acetate, Polyisobutene, 
Polysorbate 20, Caprylic/Capric Triglyceride, Hydroxyacetophenone, Phytic Acid, 
Diethylhexyl Syringylidenemalonate, Disodium EDTA, Ethylhexylglycerin, 
Phenoxyethanol  
 
SkinMedica Rejuvenative Moisturizer: Water/Aqua/Eau, Caprylic/Capric 
Triglyceride, Tocopheryl Acetate, Diglycerin, Isostearyl Behenate, Glyceryl 


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Stearate, PEG-100 Stearate, Tetrahexyldecyl Ascorbate, Butyrospermum Parkii 
Butter, Panthenol, Phytosterols, Tocopherol, Tocotrienols, Squalene, Oryza 
Sativa Bran Cera, Aloe Barbadensis Leaf Juice, Algae Extract, Bisabolol, Ginkgo 
Biloba Leaf Extract, Avena Sativa Kernel Extract, Sodium Hyaluronate, Stearyl 
Glycyrrhetinate, Retinyl Palmitate, Glycerin, Glyceryl Polyacrylate, Dimethicone, 
Cetyl Alcohol, Cetearyl Alcohol, Ceteareth-20, Caprylyl Methicone, Carbomer, 
Tromethamine, Disodium EDTA , Potassium Sorbate, Phenoxyethanol, 
Ethylhexylglycerin, Parfum/Fragrance 
 
 
SkinMedica Essential Defense Mineral Shield Broad Spectrum SPF 35 
Sunscreen: Water, Cyclopentasiloxane, Dimethicone, Polyglyceryl-3 
Polydimethylsiloxyethyl Dimethicone, Butylene Glycol, Aluminum Hydroxide, 
Dimethicone/PEG-10/15 Crosspolymer, PEG-9 Polydimethylsiloxyethyl 
Dimethicone, Sodium Chloride, Caffeine, Camellia oleifera Leaf Extract, Sodium 
Citrate, Dimethicone/Vinyl Dimethicone Crosspolymer, Triethoxysilylethyl 
Polydimethylsiloxyethyl Hexyl Dimethicone, Stearic Acid, Ethylhexylglycerin, 
Phenoxyethanol 
 
Test Product B (4% Hydroquinone Topical Prescription Cream): 
 
[Ingredients TBD depending on Pharmacy] 
 
4.3 Subject Compliance 
Subject compliance to the study treatment regimen will be verbally assessed; 
study personnel will ask each subject whether they missed any applications of 
study treatment since the previous visit and will quantify the subject’s response. 
 
4.4 Concomitant Medications 
Systemic and topical medications being used at baseline that are considered 
necessary for the subject’s welfare and will not interfere with the study may be 
used.  Administration of these drugs must be reported on the appropriate case 
report form and any alterations in the use of the medication during the study will 
be carefully noted.  Administration of a prohibited drug (see section 4.2 of 
protocol) in an emergency situation is done with the safety of the study 
participant as the prime consideration.  All topical and systemic medications that 
the subject receives during the study will be recorded.  Any alterations will be 
noted. 
 
 
4.5 Treatment Group Randomization 
Subjects will be randomized in a 1:1 fashion to receive treatment with 
SkinMedica’s cosmetic topical brightener or 4% hydroquinone. A randomization 
table will be provided by the sponsor and used to determine which facial side will 
be treated with Test Product A (cosmetic topical serum “Lytera 2.0”) and Test 
Product B (4% hydroquinone) for each subject.  


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6.0 ASSESSMENTS  
6.1 Clinical Grading of Efficacy Parameters 
 
Clinical grading of the efficacy parameter will be performed at the study visits indicated. 
Hyperpigmentation will be assessed on the left and the right side of each subject’s 
face separately. 
 
Melasma Severity Rating Scale: 


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At the screening/baseline visit and the end of treatment visit (week 12), the 
Invesgator will assess the subject’s facial skin for the severity of symmetrical 
facial melasma using the following Melasma Severity Rating Scale on the left and 
right facial sides. Subjects must present with a score of 2 for the left and the right 
facial sides to be enrolled into the study. 
 
 
 
Score 
Hyperpigmentation Status 
0 
Cleared: color of melasma lesions 
approximately equivalent to 
surrounding normal skin or with 
minimal residual hyperpigmentation 
1 
Mild: color slightly darker than the 
surrounding normal skin 
2 
Moderate: color moderately darker 
than the surrounding normal skin 
3 
Severe: color markedly darker than 
the surrounding normal skin 
 
 
Overall Hyperpigmentation Scale: 
At all visits (baseline, weeks 4, 8 and 12), the Investigator will globally assess the 
subject’s left and right facial sides for overall hyperpigmentation using the 
following ten point scale (0 – 9): 
None 
(Score of 0) 
 
Skin is normal in color with no evidence of 
hyperpigmentation 
 
Mild  
(Score of 1, 2 or 3) 
Several brown spots with increased pigmentation; they are 
small in size and slightly darker than surrounding skin 
Moderate 
(Score of 4, 5 or 6) 
Many brown spots with increased pigmentation; they are 
medium in size and much darker than surrounding skin 
Severe 
(Score of 7, 8 or 9) 
Many large brown spots with increased pigmentation; they 
are large in size and markedly darker than surrounding skin
 
 
Half-face Evaluation of Melasma Area Severity Index (MASI) Score 


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At all visits, (baseline, weeks 4, 8 and 12), the Investigator will assign a grade for 
the left and right facial sides, for each of the below units, for the variable A 
(percentage of each area involved), D (darkness of pigment) and P (pattern of 
involvement), as described in detail below.   
Calculations will be conducted by the sponsor upon receipt of the completed 
CRFs. 
3 variables are assessed for each half- facial unit: 
- 
Total Area Involved (A) 
- 
Darkness of pigment (D)  
- 
Homogeneity (H) 
 
Variable Definitions: 
A = A numerical value is assigned for the corresponding percentage of the 
total area of the facial segment being assessed.  
This value represents ONLY the percent of the area involved, not the pattern or 
darkness of the pigment. 
0=  No involvement 
1= <10% involvement 
2= 10-29% involvement 
3= 30-49% involvement 
4= 50-69% involvement 
5= 70-89% involvement 
6= 90-100% involvement  
 
D = Darkness of the pigment compared to adjacent normal pigment.  
0= Normal skin color  
1= Slightly darker than normal color 
2 = Mild hyperpigmentation 
3= Modrate hyperpigmentation,clearly and distinctly darker than normal 
pigment 
4 = Severe hyperpigmentation,virtually black pigment  
 
H = The homogeneity of the pigmentation will be assessed using the below 
scale: 
0= Normal skin color without evidence of hyperpigmentation 
1= Specks of involvement  
2 = Small patchy areas of involvement < 1.5 cm diameter  
3 = Patches of involvement> 2 cm diameter  
4 = Uniform skin involvement without any clear areas  
 


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Calculation of the half-face MASI score:  
To calculate the half-face MASI score, the sum of the severity grade for darkness 
(D) and homogeneity (H) is multiplied by the numerical value of the areas (A) 
involved and by the percentages of the four facial areas (10-30%). 
 
Total Half-Face MASI score:  
Half Forehead 0.15(D+H)A + One Malar Side 0.3 (D+H)A + Half Chin 
0.05(D+H)A 
 
 
Investigator’s Global Improvement Assessment- Overall 
Hyperpigmentation: 
 
The expert grader will also score an Investigator’s Global Improvement 
Assessment for Overall Hyperpigmentation on the left and right facial sides at all 
follow-up visits (weeks 4, 8, and 12). 
0=No change or worsening 
1=Mild improvement (~25% overall improvement) 
2=Moderate improvement (~50% overall improvement) 
3=Marked improvement (~75% overall improvement) 
4=Complete clearing/Dramatic improvement (~95%+ overall improvement) 
 
6.2 Investigator’s Tolerability Assessment 
Tolerability of the test products will be assessed through the capture of adverse events 
reported throughout the study period. Any adverse event(s) experienced by the subject 
during the study period, whether related to the treatment or not, will be recorded in the 
“Case Report Form.” 
6.3 Subject MELASQOL Assessment  
Subjects will complete the MELASQOL assessement regarding the left and their right 
facial sides at the baseline visit and at week 12 only. The MELASQOL is a validated 
assessment to help measure the emotional and psychological impact of melasma (3).  
This questionnaire is found in 
.  
 
6.4 Subject Self-Assessment Questionnaires  
Subjects will complete a Sponsor-provided self-assessment questionnaire at follow-up 
visits at weeks 4, 8, and 12. The assessment consists in a personal and subjective 
evaluation of the facial skin quality during and after the treatment by the subject. In 
addition, the assessment serves to evaluate the self-perceived cosmetic efficacy of the 
treatment and the product attributes. This questionnaire is found in 
 
 
6.5 Imaging Procedures 
Photographs will be taken at all visits utilizing standardized conditions for all subjects.  


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The skin must be cleansed prior to photography to remove any makeup, including 
foundation makeup, lipstick/gloss and eye shadow. The settings for the exposure, 
lighting, flash, and focal length will be maintained constant over the course of the study.  
 
Ensure that subjects jewelry is removed from ears/neck and hair is pushed back away 
from the face, ensuring that no stray hairs are in the facial area. 
Subjects will be photographed using an appropriate clinical digital photography system 
 at highest resolution in a 
consistent position. Importantly, the photography should be taken to enable comparison 
of baseline photos with later photos taken at the end of the treatment period. For 
instance, if available, the overlay function must be used. As each photograph is being 
taken, it should be viewed to ensure that it is in focus and is similar to its baseline 
counterpart in all technical aspects, including lighting, distance and angle. In addition, 
the face should be captured in neutral facial expressions and neutral angles (e.g., 
avoiding hypo- or hyperextension of the neck).  
 
Photos using the 
 will be taken from three angles to enable the improvement to 
be clearly noticed: full frontal (0°) and at profile from the left (45°) and from the right side 
(45°). Photos will be taken at controlled distances under standard room lighting. Cross-
polarized, parallel- polarized and visible light images will be acquired along with both 
blue fluorescence and ultraviolet fluorescence images. During the photography, the 
subjects will be asked to keep their eyes closed. 
 
6.6 Mexameter Instrumentation Procedures 
Two target hyperpigmented lesions will be selected from the left (1) and the right (2) 
malar facial areas and measured by the mexameter, and instrument that measures 
melanin content. Measurements at subsequent visits must be taken from the same 
target lesion locations as at the baseline visit within each subject. 
One target “normal” measurement will also be taken from an unaffected skin area on 
the face representing normal skin. The values from the target hyperpigmented lesions 
will be compared to the normal lesion value. 
 
7.0  STATISTICS 
Statistical analyses will be conducted by the sponsor on an intent-to-treat basis (ex: all 
enrolled subjects, with at least one follow-up visit, will be included in the analysis).   
 
8.0 RESPONSIBILITIES OF THE INVESTIGATOR 
8.1 Adherence to the Study Protocol 
The Investigator must ensure adherence to the procedures outlined in this Study 
Protocol.  The procedures set out in this study protocol, pertaining to the conduct, 
evaluation, and documentation of this study, are designed to ensure that the 
Investigator abides by GCP as described in the ICH Guidelines Topic E6: 


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“Guideline for Good Clinical Practice.”  Compliance with these regulations also 
constitutes compliance with the ethical principles described in the current revision 
of the Declaration of Helsinki.  The study will also be carried out in keeping with 
local legal and regulatory requirements. 
 
8.2 Data Handling and Record Keeping 
The Investigator must ensure that proper source documentation for all study 
activities are diligently maintained and securely kept.  The Investigator will 
transfer all relevant data to the Case Report Form as stipulated in this Study 
Protocol and his/her signature on the Case Report Form guarantees 
completeness and integrity of these data.  The Investigator will store all study 
related supplies in a secure and locked location. In addition, the Investigator will 
ensure that all Case Report Forms will be maintained for a period of two years 
after the conclusion of the study. 
 
9.0 REGULATORY OBLIGATIONS 
9.1 Institutional Review Board 
The study protocol, informed consent forms (all versions), and any specific 
advertising will be submitted to and approved by Independent Investigational 
Review Board before the start of the study.  A form must be signed by the 
chairman or designee of the IRB noting the approvals. This notification will be 
provided to SkinMedica for notification of study initiation. 
 
9.2 Protocol 
The Investigator signing the protocol signature page will act as the Principal 
Investigator at this site. Protocols will be noted as approved by the Investigator 
by placement of his signature on the Investigator’s Signature Page.  Copies of 
the IRB approved protocol and informed consents will be provided to 
SkinMedica. 
 
9.3 Informed Consent 
An Informed Consent Form (ICF) that includes all of the relevant elements 
currently required by FDA or state regulations will be provided to each 
prospective study subject at screening and before enrollment into the study.  The 
type and method of study, any potential or possible hazards, and the subject’s 
right to withdraw from the study at any time will be explained to the subjects by 
the Investigator or Designee. Once the Investigator or Designee is assured that 
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the subject will be asked to give consent by signing and dating in the appropriate 
areas of the Informed Consent Form.  The Investigator or Designee will also sign 
and date the ICF.  A copy of the IRB approved ICF will be given to the subject for 
the subject’s records and the original will be filed in the subject’s binder or folder. 
 
9.4 Protocol and Informed Consent Changes 
Changes to the protocol or Informed Consent Forms will be implemented as 
amendments to the original document and approved by the IRB.  The approvals 
will be processed in accordance with the established IRB procedures.  Copies of 
all protocol and ICF amendments/revisions, along with letters noting IRB 
approval, will be submitted to SkinMedica, as this may affect safety.  Any 
addenda, amendment or revision that substantially alters the study design or 
increases potential risk to the subject will require the subject’s consent to 
continue in the study. 
 
9.5 Study Monitoring 
The site will be responsible for internal verification of complete and accurate data 
collection and confirming adherence to the protocol throughout the study. The 
study may be monitored by Sponsor representatives to ensure that the protocol 
and GCP guidelines are being followed and to assist in resolving any difficulties 
encountered while the study is in progress. The monitoring may include site visits 
and frequent communications (telephone, fax, email, letters). 
 
10.0 CONFIDENTIALITY OF RECORDS 
 
Information about the subject’s health taken during this study may be used and given to 
others by the study coordinators, the medical staff, the respective study center and by 
the subject’s doctors and their other healthcare providers. The subject’s doctors and 
their healthcare providers may share health information about the subject with the 
investigator and study coordinator. The study coordinator and the providers may share 
that information with researchers participating in this study’s laboratories conducting 
tests for this study. A final study report may be shared with SkinMedica, Inc.; The U.S. 
Food and Drug Administration (FDA); Department of Health and Human Services 
(DHHS) agencies; other U.S. and foreign government agencies that watch over quality, 
safety and effectiveness of research. 
 
All research related personnel will ensure subject confidentiality is maintained. All 
subject related documents will be identified by subject initials and subject identification 
numbers. All subject related documents will be filed in individual subject binders or 


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folders and stored in confidence by the site only to be accessed by research related 
personnel. 
 
11.0 DELEGATION OF INVESTIGATOR RESPONSIBILITIES 
 
The Investigator should ensure that all persons assisting with the trial are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and 
their trial-related duties and functions.  The investigator should maintain a list of sub-
investigators and other appropriately qualified persons to whom he has delegated 
significant trial-related duties. 
 
12.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The Investigator must ensure that institutional regulations, the Informed Consent Form, 
and the HIPAA Authorization clearly permit study-related monitoring, audits, IRB review, 
and regulatory inspections providing direct access to source data and documents. 
 
13.0 ADVERSE EVENTS AND REPORTING 
 
13.1 Serious And/Or Adverse Event Reporting 
A serious adverse event is any untoward medical occurrence, that, at any dose: 
 results in death; 
 is life-threatening; 
 requires in-subject hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity;  
 is a congenital anomaly/birth defect; or 
 is an important medical event. 
 
Throughout the study, subjects will be monitored for signs and symptoms of 
adverse events.  An adverse event is any pathological or unintended change in 
the structure, function or chemistry of the body that occurs during the study, 
irrespective of causality, including any illness, injury, toxicity, sensitivity, or 
sudden death.  The condition must either not be present pre-study or must 
worsen in either intensity or frequency during the study. 
 
An unanticipated adverse study drug event is any drug-related adverse event, 
which is not identified in nature, severity, or frequency in current literature on the 
test article. 
 


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All adverse events, including serious and study drug related or unanticipated 
adverse drug events, must be recorded and assessed by the Investigator.  In the 
event of an adverse event, serious adverse event or unanticipated adverse drug 
event, the physician will provide optimal subject care. 
 
Subjects who have had a serious adverse event must be followed clinically until 
all parameters, including laboratory values, have either returned to normal or are 
otherwise explained. 
 
Any serious adverse event or unanticipated adverse drug event occurring in this 
study will be analyzed and identified by the investigator and reported to the IRB 
within 10 business days, as per IND regulations and FDA Guidance. The 
investigator will also determine the event related to the study drug and report that 
event to the manufacture of the device, if necessary. 
 
Serious adverse events will be reported to the Sponsor within 24 hours (or the 
next working day). The main Sponsor contact for serious adverse events is: 
 
If death was the outcome of the event on the initial SAE Report, a Follow-
up/Final Report, including autopsy report, when performed, must be completed. 
 
13.2 Pregnancy During The Study 
If a subject of childbearing potential becomes pregnant at any time while 
participating during the study, the pregnancy will be deemed an Adverse Event 
and the subject will stop all protocol related procedures. The investigator will 
follow-up with the subject until the pregnancy reaches term or until the pregnancy 
has been resolved. 
 
The Investigator will report the Adverse Event of pregnancy to the IRB within 24 
hours of awareness of the event and follow-up reports will be filed with the IRB 
as information with changes of the pregnancy becomes available. 
 
13.3 Anticipated Reactions 
All test materials have the potential to cause some minor side-effects or other 
reactions. Possible reactions to the test material(s) may include (but are not 
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scaling/dryness, and redness. Additionally, test material(s) applied to the eye 
areas have the potential to cause eye watering/tearing, redness of the eyes, 
corneal erosions, and foreign body sensation in the eyes.  
 
Symptoms of mild to moderate irritation, including the examples discussed 
above, will not be treated as adverse reactions if they are mild in nature. These 
conditions may or may not resolve over time. Symptoms that are persistent and 
moderate to severe in nature, or that involve elevation (e.g. edema, papules, 
vesicles, spreading) will be considered AEs.  
In rare cases, it is possible for a subject to develop allergic reactions to the test 
material(s). This risk is increased for individuals with a history of allergies, and 
individuals with asthma and/or a history of hives may also be affected. Subjects 
will be instructed to notify the clinic immediately if they experience an allergic 
reaction including rash, hives, and itching.  
The Investigator or designee will have the final authorization to determine if a 
reaction will be considered an AE.  
 
13.4 Unknown/Unforeseeable Risks 
In addition to the risks listed above, there may be some unknown or infrequent 
and unforeseeable risks associated with the use of the assigned study products. 
Subjects will be informed both verbally and in writing in a timely manner of any 
new information, findings or changes to the way the research will be performed 
that might influence their willingness to continue their participation in this study. 
 
Pregnancy/Fetal Risks:  The effects of SkinMedica Facial Cleanser, Rejuvenative 
Moisturizer, Essential Defense Mineral Shield Broad Spectrum SPF 35, Test 
Product A (Lytera 2.0) and Test Product B (4% Hydroquinone) have not been 
studied in pregnancy and therefore may be hazardous.   
 
If a subject thinks that she may be pregnant or have become pregnant during the 
study she is to inform the study doctor immediately. If a subject becomes 
pregnant or thinks they may be pregnant, they will be removed from the study 
and the study doctor will refer the subject to seek obstetric care and may request 
to track their pregnancy and will report  to the IRB. 
 
13.5 Unblinding 
In the event that a subject experiences an Adverse Event or Serious Adverse 
Event, the Investigator and/or Sub-Investigator will become unblinded. 
 
14.0 REFERENCES 
1. Melasma: a clinical and epidemiological review* Ana Carolina Handel, Luciane 
Donida Bartoli Miot, and Hélio Amante Miot, An Bras Dermatol. 2014 Sep-Oct; 
89(5): 771–782. 


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2. Melasma. Etiologic and Therapeutic Considerations, Pearl E. Grimes, MD, Arch 
Dermatol. 1995;131(12):1453-1457. 
3. Development and validation of a health-related quality of life instrument for 
women with melasma. R. Balkrishnan, et.al. Br J Dermatol. 2003;149:572-577. 
 
 


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