Clinical trial NCT00616239
Conditions: Melasma
Keywords: Melasma Dark spots on the face
Sponsor: University of Texas Southwestern Medical Center
Start date: 2008-01-01; Completion date: 2018-03-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will enroll 20 adult Hispanic women. Participants will apply 4% hydroquinone cream twice daily to affected areas on the face for 14 weeks and half the face will be peeled with 20-30% salicylic acid every two weeks for a total of 4 peels. The first two peels will be 20% salicylic acid and the second two peels will be with 30% salicylic acid. The purpose of the study will be to evaluate the safety and efficacy of salicylic acid combined with 4% hydroquinone versus 4% hydroquinone alone.

Detailed description:

Arms: arm 1: Subjects randomized to have the right side of the face peeled with salicylic acid every 2 weeks for a total of 4 peels (first 2 at 20% and last 2 at 30%). Subjects will apply 4% hydroquinone cream to affected areas on entire face for 14 weeks. arm 2: Subjects randomized to have the left side of the face peeled with salicylic acid every 2 weeks for a total of 4 peels (first 2 at 20% and last 2 at 30%). Subjects will apply 4% hydroquinone cream to affected areas on entire face for 14 weeks.
Interventions: intervention 1: 20-30% Salicylic Acid peels to the right side of the face intervention 2: 20-30% Salicylic Acid peels to the left side of the face
Intervention descriptions: intervention 1: Two 20% salicylic acid peels two weeks apart followed by 2 30% salicylic acid peels two weeks apart to the right side of the face. intervention 2: Two 20% salicylic acid peels two weeks apart followed by 2 30% salicylic acid peels two weeks apart to the left side of the face

Protocol documents:
Prot_SAP_000.pdf: 
The efficacy of salicylic acid peels in combination with 4% hydroquinone cream versus 4% 
hydroquinone cream alone in the treatment of melasma in Hispanic women 
 
 
Institution: 
The University of Texas Southwestern Medical Center at Dallas, 
Department of Dermatology 
Author(s): 
Sreedevi Kodali, MD and Amit G. Pandya, MD 
Contact Information: 
Address: 5323 Harry Hines Blvd., Dallas, TX 75390-9190 
Ph: (214) 645-8971 (office hours) ph: (214) 645-2400 (after hours) fax: 
(214) 648-5777 
email: amit.pandya@utsouthwestern.edu, skodal@parknet.pmh.org 
 
 
Table of contents* 
1 
Schema .................................................................................................................................................... 2 
2 
Study Objectives ...................................................................................................................................... 2 
3 
Background .......................................................................................................................................... 2-3 
4 
Agent ....................................................................................................................................................... 3 
5 
Eligibility Criteria ................................................................................................................................. 3-4 
 
6 
Material and data to be accessioned  .................................................................................................... 4-5 
7 
Treatment.............................................................................................................................................. 5-6 
8 
Evaluation Criteria .................................................................................................................................. 6 
9 
Off-study Criteria ................................................................................................................................. 6-7 
10 Registration and study monitoring .......................................................................................................... 7 
11 Statistical Consideration ....................................................................................................................... 7-8 
12 References ............................................................................................................................................... 9 
 
 
 
 
 
 
 
 
 
 
 
 
 


October 6, 2006 
2 
  1 
Schema 
 
Visit Number 
1 
2 
3 
4 
5 
6 
Time of Visit 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 14 
Inclusion/Exclusion 
Criteria 
    X 
 
 
 
 
 
  Informed Consent 
X 
 
 
 
 
 
Investigator Evaluation 
X 
X 
X 
 
X 
X 
Patient Evaluation 
 
 
 
 
X 
X 
Dispense 4%  
Hydroquinone,  
Cleanser, Sunscreen 
X 
 
 
 
 
 
Salicylic Acid Peel 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
2 
Study Objectives 
To assess the efficacy of salicylic acid peels every two weeks in combination with 4% 
hydroquinone versus 4% hydroquinone alone in the treatment of melasma in Hispanic women.  
This study will take place over 14 weeks in which time all patients will use 4% hydroquinone 
cream to the affected areas twice daily, but half the face will receive four salicylic acid peels 
every two weeks.  End points include change in pigmentation of skin affected by melasma 
compared to normal skin measured objectively with a mexameter and subjectively by the MASI 
score, the melasma severity assessment, and the physician and patient global evaluation.  
 3 
Background  
Melasma is a common disorder of hyperpigmentation affecting the cheeks, forehead, 
and upper lip.  It manifests as tan-brown macules/patches slowly enlarging on the face.   It 
can affect all racial types but predominately affects women of skin types IV-VI especially 
those living in areas of intense UV radiation (1).    
The exact etiology of melasma is unknown, but it is thought to be multifactorial.  
Known triggers/exacerbators include pregnancy, hormone therapy, and sunlight.  Melasma 
can be very difficult to treat and often frustrating for the patient and physician.  A recent 
study has shown in Hispanic women that melasma significantly affects quality of life in both 
personal and professional aspects (2).       
Conventional treatments thus far include elimination of causative factors and a 
hypopigmenting agent, typically 4% hydroquinone either alone or in combination with a 


October 6, 2006 
3 
retinoid, topical steroid or superficial peeling agents.  In addition, patients are advised to use 
a sunscreen and take other sun protective measures (1).   
  Patients with melasma may significantly benefit from the addition of biweekly 
salicylic acid peels to 4% hydroquinone cream. A previous, uncontrolled study showed that 
salicylic acid peels of 20% to 30% at two week intervals in patients with skin types V-VI 
resulted in moderate-significant improvement in melasma in 4 of 6 patients with melasma (3). 
Although hydroquinone is the standard of care for melasma, no controlled trials have been 
performed comparing the efficacy of salicylic acid peels in combination with 4% 
hydroquinone versus hydroquinone alone.   
4 
Agents 
The two agents used in this study will be salicylic acid 20-30% peels and 4% 
hydroquinone cream, both of which are FDA approved for melasma.   
 
The 4% hydroquinone cream will be purchased as a generic cream formulation.  Patients 
will apply this cream twice a day to affected areas on both sides of the face.  Contraindications to 
the use of 4% hydroquinone include pregnancy, plans for pregnancy, or breast feeding (in all 
cases patients will be excluded from our study).  Side effects can include irritation, redness, 
pruritus, and hypo/hyperpigmentation.  One study comparing the use of 4% hydroquinone with 
placebo found no significant difference between the two groups in terms of incidence of side 
effects (4). 
 
The salicylic acid peels will also be purchased from a medical supply company in both 
20% and 30% concentrations.  Patients will receive 4 peels total at 2 week intervals.  The first 
two peels will be 20% and the last two peels will be 30%.  Side effects may include redness, 
irritation, pruritus, skin peeling, and hypo/hyperpigmentation.  One study looked at the safety and 
efficacy of salicylic acid peels in darker racial-ethnic groups and found the above mild side 
effects to occur in ~16%, all of which were transient, resolving in less than two weeks (3).   
 
5 
Eligibility Criteria 
 
Consenting Hispanic women with bilateral moderate-severe epidermal or mixed melasma 
will be enrolled in this study.  This study will be limited to only Hispanic women due to the high 
frequency of melasma in this population and in order to study a uniform population.  Spanish 


October 6, 2006 
4 
speaking patients will be eligible for this study and a Spanish consent/HIPAA forms will be 
provided to them.  In addition, someone who speaks Spanish will always be available to answer 
questions.  Key exclusion criteria include pregnancy, breastfeeding an infant, use of 4% 
hydroquinone cream within three months of the study, and history of chemical peels, 
microdermabrasion, or facial laser treatment within 9 months of the study.    
 
6 
Material and data to be accessioned 
 
Thirty adult Hispanic women with moderate to severe melasma, diagnosed by clinical 
criteria, will be recruited to participate in this study.  Accounting for ~ 10 screening failure, we 
hope 20 patients will be able to complete this 14 week prospective investigator blinded, split-face 
trial of biweekly salicylic acid peels in combination with 4% hydroquinone versus 4% 
hydroquinone alone.   
 
At the initial visit, patients will be asked for their past medical history, current 
medications, and will undergo a urine pregnancy test.   Once it is determined that patients are 
eligible for the study, they will be asked to give informed written consent and sign a HIPAA 
authorization.  Next they will undergo evaluation of their melasma by the study investigator 
which includes an objective measurement of the darkness of their melasma by mexameter (an 
electronic device which painlessly measures skin pigmentation, 0-white, 1000-black, by placing a 
probe on the skin) compared to nearby normal skin.  In addition, a MASI score will be calculated 
(a subjective score based on darkness, area of involvement, and homogeneity of the pigment).  A 
melasma severity assessment will also be performed by the physician which rates the severity of 
the melasma on each of side of the face according to the following numerical scale: 0 for clear, 1 
for mild, 2 for moderate, 3 for severe.  Standard and polarized photographs (a specialized 
photograph that enhances the appearance of hyperpigmentation) will also be taken.  Patients will 
then undergo a 20% salicylic acid peel to half the face (side to be peeled will be determined by a 
computer generated randomization code).  In addition they will be given 4% hydroquinone to use 
on the affected areas twice a day (X 14 weeks) and a cleanser and sunscreen to be used daily.  No 
other medications for melasma will be allowed during the study period.  
 
At week 2, patients will undergo another 20% salicylic acid peel to half the face.  They 
will be asked to report any adverse events from the salicylic acid peels or the hydroquinone.  
Prior to the peel a mexameter reading will be taken and the MASI score calculated for each side 
of the face. 


October 6, 2006 
5 
 
At week 4 and 6 patients will undergo 30% salicylic acid peels and be asked to report any 
adverse events.  In addition, the study investigator will take mexameter readings from the 
peeled/unpeeled sides and calculate a MASI score on both the peeled/unpeeled sides at week 4 
(investigator will be blinded as to which side was peeled).  At weeks 8 and 14, patients will report 
any adverse events and the study investigator will take mexameter readings and calculate a MASI 
score as above.  The physician will also perform a melasma severity assessment for each side of 
the face at weeks 8 and 14.  In addition, at 8 and 14 weeks, both the physician and patient will 
perform a subjective global evaluation of which side, if any, had more improvement in the 
following terms: no change/slight/moderate/marked.  
Visit Schedule and Assessments   
 
 7 
Treatments 
Investigational Therapy and Reference Therapy 
Investigational Agent – salicylic acid peels (20-30%) applied every two weeks for a total of four 
peels 
Reference Therapy – hydroquinone 4% cream applied BID X 14 weeks.  
Treatment Assignment, Blinding, and Randomization 
Patients will all be given 4% hydroquinone to use on the affected areas for 14 weeks.  In 
addition, each patient will receive biweekly salicylic acid peels to half of the face for a total of 
four peels (at week 0, 2, 4, 6).  The first two peels will be 20% salicylic acid and the last two 
peels will be 30% salicylic acid.  The side to be peeled will be determined by a computer 
generated randomization code.  Only the investigators will be blinded in the study, due to the 
Visit Number 
1 
2 
3 
4 
5 
6 
Time of Visit 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 14 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Information & Informed Consent 
X 
 
 
 
 
 
Investigator Evaluation 
X 
X 
X 
 
X 
X 
Patient Evaluation 
 
 
 
 
X 
X 
Dispense Hydroquinone 4%,           
  cleanser, sunscreen 
X 
 
 
 
 
 
Salicylic Acid Peel 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 


October 6, 2006 
6 
nature of the treatments it will not be possible for the patients or the nurse performing the peels to 
be blinded.   
No concomitant therapy will be allowed for the duration of the study.  Patients who were 
already on an oral contraceptive pill will be allowed to continue the pills during the study, but 
oral contraceptive pills may not be introduced during the study. 
Interruption or Discontinuation of Treatment 
Every patient has the right to discontinue study participation at any time, and every 
patient may be discontinued from the study for any reason beneficial to his/her well being. All 
data generated up to the time of discontinuation from the study will be analyzed and the reason(s) 
for discontinuation will be recorded.  
Treatment Compliance 
Patients will be asked to return all unused medication at the end of the study and the 
quantity of returned medication will be documented. 
8 
Evaluation Criteria 
 
Patients satisfying inclusion criteria will be chosen to participate in the study.  The degree 
of pigmentation will be noted at baseline by mexameter readings taken on both sides of the face 
on affected skin and also nearby normal skin.  Additional mexameter readings will be taken at 
weeks 2, 4, 8, and 14.  In addition standard and polarized photographs will be taken at baseline 
and at weeks 8 and 14.  A MASI score will also be calculated at baseline and at weeks 2, 4, 8, and 
14.  A melasma severity assessment will be performed by the physician at baseline and at weeks 8 
and 14.  A physician and patient global assessment will be performed at weeks 8 and 14, a 
subjective measure of which side, if any, improved more and to what degree (no 
change/slight/moderate/marked).  Primary efficacy assessment will be improvement of melasma 
using mexameter readings while secondary assessment will be improvement in MASI scores, 
melasma severity assessment, and physician and patient global improvement compared with the 
opposite side. 
9 
Off-study criteria 
Safety assessments will consist of monitoring and recording all adverse events, including 
serious adverse events.  An adverse event is any undesirable sign, symptom or medical condition 
occurring after starting the study drug (or therapy).  Medical conditions/diseases present before 
starting the study treatment are only considered adverse events if they worsen after starting the 
study treatment.  As this study only involves topical therapy, the most likely adverse events are 


October 6, 2006 
7 
minor and may include irritation, redness, burning, skin peeling, and  hyper/hypopigmentation.  
These adverse events will be specifically monitored for by using investigator observed evaluation 
and patient reporting.  The patient will be specifically queried upon each visit regarding adverse 
events from the salicylic acid peels and/or the 4% hydroquinone cream.  A patient has the right to 
discontinue participation in the study at any time.  The study investigator also has the right to 
discontinue the patient’s participation in the study should the patient’s condition worsen, they are 
unable to follow the treatment schedule, or the patient has unexpected side effects from the study 
medications.  
A serious adverse event is an undesirable sign, symptom or medical condition which: 1) 
is fatal or life-threatening, 2) requires or prolongs hospitalization, 3) results in persistent or 
significant disability/incapacity, 4) constitutes a congenital anomaly or a birth defect, or 5) is 
medically significant, in that it may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
All adverse events will be reported to the principal investigator.  All unexpected or 
serious adverse events will also be reported to the IRB.    
10 
Registration and study monitoring 
Once patients are recruited into the study and complete their initial evaluation, they will 
be given a schedule of follow up visits.  As indicated in the schedule above, at each subsequent 
visit, they will be asked about adverse events, and they will be evaluated by a study investigator.  
All information will be recorded in the study report forms.  All adverse events will be reported to 
the principal investigator, and all unexpected or serious adverse events will also be reported to the 
IRB.    
11 
Statistical Considerations   
Investigators will enter the information required by the protocol into the Study Report 
Forms (SRFs).  Additionally, a series of standardized photographs will be taken of each patient at 
baseline and 14 weeks to provide permanent documentation. 
The objective of this trial is to study the efficacy and tolerability of salicylic acid peels in 
the treatment of melasma in Hispanic women. The data will be summarized with respect to 
efficacy and safety observations. Data will be presented for the complete intent-to-treat 
population (all patients having taken at least one dose of study medication) as well as the per-
protocol population (all patients who completed the study without major protocol deviations).  


October 6, 2006 
8 
The assessment of safety will be based mainly on the frequency of adverse events, which 
includes all serious adverse events. Adverse events will be summarized by presenting for each 
treatment group the number and percentage of patients having any adverse event, having an 
adverse event in each body system, and having each individual adverse event. Any other 
information collected (e.g. severity or relatedness to study medication) will be listed as 
appropriate.   
Efficacy will be primarily assessed by comparing delta mexameter readings (affected 
skin-nearby normal skin) on the peeled versus unpeeled side.  This data will be analyzed using a 
two factor repeated measures analysis of variance.  Efficacy will be secondarily assessed by 
change in MASI score on the peeled versus unpeeled side also using the repeated measures 
analysis of variance.  Another secondary measure of efficacy will be the melasma severity 
assessment of the peeled versus unpeeled side also using the repeated measures analysis of 
variance.   
 
A McNemar chi-squared test will be used to determine if there is agreement between the 
Physician and Patient Global Assessment of Improvement at 8 and 14 weeks as to which side 
appears more improved.  For those in which there is agreement, we will further look at the degree 
of agreement and use the McNemar chi-squared test to see how well they correlate.  The critical 
value for all efficacy, tolerability, and subject satisfaction survey analyses will be 0.05. 
 
A previous study has shown that using 4% hydroquinone cream alone results in total 
improvement in melasma in ~40% of patients (4).  However, the assessments of melasma 
improvement were more subjective than objective in nature and differ from the end points we are 
using in our study.  Furthermore, it is unclear how much more improvement we may see with the 
addition of the salicylic acid peels.  Since we do not know how much improvement to expect 
given our efficacy endpoints, we will be performing a pilot study recruiting ~20 patients. 
   
 
 
 
 
 
 
 
 
 


October 6, 2006 
9 
12              References 
1. Grimes PE.  Melasma.  Etiologic and therapeutic considerations. Arch Dermatol.  1995; 
131: 1453-7. 
2. Dominguez AR, Balkrishnan R, Ellzey AR, Pandya AG.  Melasma in Latina patients: 
Cross cultural adaptation and validation of quality-of-life questionnaire in Spanish 
language.  J Am Acad Dermatol. 2006; 55: 59-66. 
3. Grimes PE.  The safety and efficacy of salicylic acid chemical peels in darker racial-
ethnic groups.  Dermatol Surg.  1999; 25: 18-22. 
4.  Ennes SBP, Paschoalick RC, Mota de Avelar Alchorne M.  A double-blind, comparative, 
placebo-controlled study of the efficacy and tolerability of 4% hydroquinone as a 
depigmenting agent in melasma.  J Dermatolog Treat.  2000; 11: 173-9.