A Randomized, Double Blind, Placebo-Controlled Clinical Trial of the Effects of Oral Zinc Gluconate Among Diagnosed Acne Vulgaris Patients
Phase: PHASE4
Conditions: Acne Vulgaris
Sponsor: East Avenue Medical Center, Philippines

 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized, Double Blind, Placebo-Controlled Clinical Trial of the Effects of Oral Zinc 
Gluconate among Diagnosed Acne Vulgaris patients 
 
 
 
 
 
NCT05096312 
 
Document date: Dec 19, 2018 
 
 

INTRODUCTION 
Acne Vulgaris is a common disorder of the pilosebaceous follicles characterized by 
comedones, papules, pustules, inflamed nodules, canalizing and deep, inflamed sacs usually 
occurring on areas of the body with hormonally sensitive sebaceous glands, including the face, 
neck, chest, upper back and upper arms.  Moderate to severe acne vulgaris affects around 20% 
of young people.  It persists into the 20s in 64% and into the 30s for 43% of individuals.1 Lesions 
last for years, result to permanent scarring, and have serious effects on an individual’s 
psychological health such as depression and social withdrawal. The annual years of healthy life 
lost per 100,000 people from acne in the Philippines is 50.6 in 2013.2 This shows that despite the 
known treatment regimens for acne, Filipino patients are still suffering from the effects of the 
disease. 
Acne has four main pathogenic contributors: follicular hyperkeratinization, increased 
sebum production, Propionibacterium acnes (P. acnes) within the follicle, and inflammation.3  
Treatment options for acne vulgaris include benzoyl peroxide, topical and oral retinoids, topical 
and oral antimicrobials, oral corticosteroids, and physical modalities such as acne surgery, laser 
and light therapy.3 Reports show that antibiotic resistance is a growing issue in the treatment 
regimen of acne vulgaris, making it less and less suitable for long-term treatment,4 hence other 
options that can be substitutes or adjuncts to treatment may be useful in this condition.  For 
long–term or maintenance therapy, physicians should consider effectivity, cost, and adverse 
effects. Several studies have explored the effect of oral zinc on acne vulgaris.  Since zinc is more 
cost-effective and has less adverse effects compared to most antibiotics, this may prove helpful 
for the Filipino patient in terms of safety and economy for long-term therapy. 
At present, there are no local studies using only oral zinc supplementation as an adjunct 
for the treatment of acne vulgaris. Thus, this study aims to determine the effect of oral zinc 
gluconate versus placebo on inflammatory lesions of acne vulgaris in the Filipino population.  
Furthermore, this study may also be able to provide more information for further studies towards 
non-antimicrobial treatment regimens for acne vulgaris in the Philippines. 
 
Review of Related Literature 
Acne Vulgaris is one of the most common dermatologic diagnoses affecting 
approximately 9.4% of the global population making it the eighth most prevalent disease 
worldwide.5  A significant number of adult patients continue to develop new-onset acne beyond 
the teenage years with prevalence found to be at 50-54% in females and 40-42.5% in males.6 
Moreover, the prevalence of acne did not substantially decrease until after the age of 44.7  Since 
acne vulgaris is a chronic and persistent skin condition, safe and effective long-term maintenance 
therapy is often required. Antibiotic resistance in acne vulgaris can occur in P. acnes and other 
organisms, creating an increase in more pathogenic strains of these bacteria.4 Given the gravity 
of the consequences of this trend, it is a challenge to maximize use of non-antimicrobial therapy 
when treating acne.4  Other options for treatment of moderate to severe acne vulgaris are 
already being explored.  A study by Stein Gold et al has shown that the fixed combination of 
adapalene 0.3%/ benzoyl peroxide 2.5% is an effective and safe single-agent topical therapy for 
moderate and severe inflammatory acne.8,9 
Oxidative status has been implicated in the pathogenesis of several skin diseases, 
including acne. A study measured oxidative stress by taking plasma levels of catalase (CAT), 

superoxide dismutase (SOD), total antioxidant capacity (TAC), and malondialdehyde (MDA). MDA 
in acne patients were significantly higher as compared with that of the controls, whereas 
activities of the antioxidant enzymes SOD and CAT were lower. Hence, this suggests that oxidative 
stress plays a key role in acne vulgaris.10 
Zinc is present in all body tissues and has been shown to have antioxidant properties.11  It 
is an essential element of more than 200 metalloenzymes, including the antioxidant enzyme, 
superoxide dismutase, and it has the ability to effectively decrease reactive oxygen species, a key 
factor in oxidative stress.12  Zinc also contributes to normal epithelial differentiation and 
development, protects against UV radiation, enhances wound healing, contributes to proper 
immune, reproductive and neuropsychiatric functions, and may decrease the relative risk of 
cancer and cardiovascular disease.13 
The recommended daily allowance (RDA) of zinc is 8 mg elemental zinc for adult females 
and 11 mg elemental zinc for adult males.14  The tolerable upper intake level of zinc is 40 mg 
elemental zinc for both adult males and females.14  Possible side effects related to oral zinc, 
usually from zinc sulfate, include nausea, vomiting, abdominal pain and diarrhea.14,15  According 
to Sardana et al, the effervescent preparations and zinc gluconate had better results as compared 
to zinc sulfate and citrate.16  Zinc gluconate is better tolerated by the gastric mucosa hence 
causing much less of the known adverse effects of zinc.  Zinc gluconate contains 14% elemental 
zinc, meaning a 100 mg tablet contains 14 mg elemental zinc.17,18 
Data suggest that zinc deficiency exist both in developed and developing countries, and 
several factors that may affect serum zinc levels include low intake of highly absorbable zinc in 
fresh foods, high phytate content of some staple food, pregnancy, lactation, and increased 
demands of physiological processes such as growth and sexual maturation.19  Whole blood zinc 
levels were measured from healthy subjects in relation to sex and age using atomic absorption 
spectrophotometry. Mean level of zinc obtained in whole human blood from males was 607.0 
+/- 105.3 micrograms/100 ml and in females 585.2 +/- 122.9 micrograms/100 ml. The results 
showed that males had slightly higher zinc levels but the difference was not statistically 
significant.20 
A few researches have been done in other countries comparing zinc levels in blood with 
the severity of acne.21,22  A study by Saleh done in Iraq measured trace elements in the blood, 
such as zinc and copper, and correlated it to the severity of acne vulgaris. The results showed 
that patients with severe acne had significantly lower levels of zinc.23  As shown in a study done 
in Iran, zinc levels may be related to the severity and type of acne lesions in patients with acne 
vulgaris, the relative decrease of serum zinc level in acne patients suggests a role for zinc in the 
pathogenesis of acne vulgaris.24 Another study of 173 acne patients published in the British 
Journal of Dermatology showed that retinol binding protein and serum zinc levels were 
significantly lower in severe acne.25  In an unpublished study, a significant relation of whole blood 
zinc levels with the severity of acne vulgaris was found in Filipinos, with severe acne showing 
significantly lower zinc levels.26  Some studies concluded that due to this, it might be helpful to 
give zinc supplements to acne vulgaris patients.27,28 
Zinc is still being studied and was found to have multiple uses in medicine and general 
dermatology as oral and/or topical therapy for conditions such as warts, cutaneous leishmaniasis, 
leprosy, herpes genitalis, dermatophytosis, bromhidrosis, pityriasis versicolor, acne vulgaris, 
rosacea, hidradenitis suppurativa, eczema, ulcers, and alopecia areata.29-31  Oral zinc has been 

compared to oxytetracycline in a study by Michaelsson et al, and showed no significant difference 
in the effect on acne vulgaris.32  On the other hand, a study by Dreno et al showed that 
minocycline was superior to oral zinc in the treatment of acne vulgaris33 and a study by Cunliffe 
et al showed that although oral zinc was correlated with decreased inflammatory lesions, 
tetracycline has a superior effect.34  These studies compared oral zinc with antibiotics, which are 
already established treatment options for acne vulgaris.  There are some instances, however, 
when patients are already resistant to antibiotics or are reluctant to take antibiotics for long-
term.  Oral zinc for acne vulgaris may be useful for patients who cannot or do not want to take 
oral antibiotics in the long-term and for those who already have erythromycin- or clindamycin-
resistant strains of Cutibacterium acnes (Propionibacterium acnes).16  Multiple sources showed 
that when oral zinc was compared to placebo, there was a significant improvement in 
inflammation and number of acne lesions.35-41  Furthermore, adding zinc salts in vitro to culture 
media of Cutibacterium acnes (Propionibacterium acnes) reduced resistance of the bacteria to 
erythromycin.41  One of the anti-inflammatory effects of oral zinc in acne was found to be in the 
inhibition of TLR2 surface expression by keratinocytes.42  Studies about giving oral zinc gluconate 
supplements versus placebo in the Philippine setting have not yet been done. 
The inflammatory score is a grading system that measures inflammatory lesions only.  It 
includes locations such as the face, chest and back.  For each location, papules, pustules and 
nodules are counted.  A factor based on the lesion (papule=3, pustule=4, nodule=5) is used to be 
multiplied to a grade equivalent to the number of lesions.  The subtotal scores are added with a 
maximum possible total score of 144.35 
The Global Acne Grading System (GAGS) is an acne severity scale that includes six 
locations on the face, chest, and back. A factor based on surface area and distribution of 
pilosebaceous units is provided for each of the six locations, and grades are based on the type of 
lesions per area (1 for ≥ one comedone, 2 for ≥ one papule,3 for ≥ one pustule, and 4 for ≥ one 
nodule). The factor and the grade are multiplied to get a local score.  The local scores are then 
added with a maximum possible global score of 44. Acne severity is rated as mild, moderate, 
severe, and very severe with corresponding cut-off scores.43,44 
 
Research Question 
Does oral zinc gluconate supplementation improve inflammatory acne as measured by 
the inflammatory score and GAGS score in diagnosed acne vulgaris patients? 
 
Objectives 
 
GENERAL 
• To assess the efficacy of oral zinc gluconate in the improvement of disease activity 
in diagnosed acne vulgaris patients. 
SPECIFIC 
• To determine the demographic and clinical profile of Acne Vulgaris patients 
• To determine the disease activity measured by the inflammatory score and GAGS 
score of acne vulgaris patients on initial consult, at 4 weeks, and at 8 weeks. 
• To determine if there is a significant difference in disease activity as measured by 
the inflammatory score and GAGS score among acne vulgaris patients given 
placebo and oral zinc gluconate. 

 
METHODOLOGY 
Study Design 
A randomized, double blind, placebo-controlled clinical trial was utilized for this study 
which was conducted from December 2018 to July 2019.   
 
Ethical Considerations 
The protocol will be submitted for ethical review and approval by the Technical Review 
Board and Institutional Ethics and Review Board of the East Avenue Medical Center. Informed 
consent will be obtained from the participants prior to participation in the study. All data 
collection will be done in a setting that ensures patient safety and privacy. Patient will be assured 
of the confidential nature of the patient-provider interactions. Active listening, open-ended 
questions and clarifications will be used.  
The investigators will perform physical examination of the patient to assess the severity 
classification, and any photographs that will be taken of the patient or the skin lesions will be 
subject to informed consent. No closed-circuit television or recording devices will be used in the 
rooms for interview and physical examination. 
 
The Informed Consent Process: 
Informed consent will be obtained from the participants prior to participation in the study. 
At the onset, patient will be assured of the confidential nature of the patient-provider interaction. 
The investigator will explain that to ensure confidentiality in data collection, the investigators will 
assign a code to replace patient identifiers (e.g. name). Only authorized members of the research 
team will be allowed to access the result. All pertinent records will be stored in a locked cabinet. 
The records identifying the subject will be kept confidential and will not be made publicly 
available. In obtaining and documenting informed consent, the investigator adheres to Good 
Clinical Practice guidelines and to sound ethical principles. During the procurement of the 
informed consent, the investigator will go through the informed consent form which will include 
the following: that the patient will enter into a research study, the purpose of the study, the 
procedure to be followed, the possible risks involved (skin irritation from the topical medications 
and nausea from the oral zinc) and the expected benefits (patient will be provided with free 
medications). The subject will also be provided contact details of whom to speak to if she or he 
has any questions or any concerns regarding the study. The investigator will not coerce or unduly 
influence a subject to participate or to continue to participate in a trial without their consent. It 
will be emphasized that whether the patient chooses to participate or not participate in the study, 
he or she will still receive appropriate treatment. It will also be made clear that no compensation 
will be given for participating in the study. None of the oral and written information concerning 
the trial will contain any language that causes the subject to waive or to appear to waive any legal 
rights or that releases or appears to release the investigator for liability from negligence. Active 
listening, open-ended questions and clarifications will be used. The investigator will provide the 
subject with ample time and opportunity to inquire about details of the trial and to decide 
whether or not to participate in the trial. All questions will be answered to the satisfaction of the 
subject. By signing the consent form, the subject attests that the information in the consent form 
and any other written information was accurately explained and apparently understood by the 

subject and that informed consent was freely given. At any time during the process, the subject 
can opt to refuse from participating in the study. 
 
Study Setting 
 
The study will be conducted at the Out-patient Clinic and the Skin Center of the East 
Avenue Medical Center (EAMC) Department of Dermatology.  The hospital had adequate staff 
and infrastructures to provide for the requirements of this study to be conducted properly.  
 
Study Population 
The subjects of the study included patients clinically diagnosed with acne vulgaris, aged 
18-27 years of age.  
 
Inclusion Criteria 
• Filipino patients, aged 18-27 years old 
• New patients diagnosed with Acne Vulgaris and a Global Acne Grading System 
score of at least 19 
• Able to read and write in English or Tagalog 
• Seen at the Out-Patient Department of East Avenue Medical Center Department 
of Dermatology 
 
Exclusion Criteria 
• Patients with other chronic dermatoses or systemic disease 
• Taking oral supplements or medications within the past 4 weeks 
• Patients who are pregnant or lactating 
 
Study Procedure 
1. In the Dermatology Out-Patient Department of East Avenue Medical Center, new patients 
who were diagnosed to have Acne Vulgaris, will be screened if they meet the 
inclusion/exclusion criteria.  
2. Informed consent will be obtained for those who are qualified. 
3. Patients will be given proper treatment whether they agree to participate or not. Patients 
who agree to participate will fill out an information sheet and three resident physicians 
will assess the patient’s Global Acne Grading System (GAGS) and acne inflammatory score 
on initial visit, after 1 month, and after 2 months. 
4. Patients will be given the bottle of zinc gluconate or placebo to be taken for 2 months, 
with patient education and a daily monitoring sheet.  Details of blinding and 
randomization detailed below.  Patients will be asked to follow up every 2 weeks where 
assessment and pill count will be done.  Participants will be advised to continue intake if 
there are any unconsumed capsules within the 60-day period. 
5. Data collected will be tabulated by the investigators and data analysis will be done. 
 
Definition of Variables 
Treatment arm 
In this study, patients will be randomly assigned to receive either placebo or oral zinc 
gluconate supplementation. The assignment to a treatment arm was performed randomly. 

 
Improvement in the disease activity 
This will be assessed by determining the difference in the GAGS and inflammatory scores 
of a patient at the start and at the end of the clinical trial.  The GAGS and inflammatory scores 
will be measured by the same investigators at the start and at the end of the trial. Secondary 
measures include the examiner’s assessment and patient’s self-assessment scores at the end of 
the trial. 
 
Randomization 
Allocation to either Group A (Zinc Gluconate) or Group B (Placebo) will be done using a 
computer-generated block randomization scheme (www.randomizer.org).  The randomization 
will be done by a resident physician who was not involved in the trial.  The randomization codes 
will be kept in a locked cabinet and will only be broken at the end of the study. Therefore, the 
assignments will be concealed from both participants and the investigators.  The investigator, 
also blinded, will be the one to dispense the medications to the patients. 
 
Treatment allocation and blinding 
The Solgar Zinc Gluconate 50mg will be repackaged by the TARC Pharmacy Laboratory of 
the University of Santo Tomas into the clear size 0 capsules. The same laboratory will prepare the 
placebo capsules and package the cornstarch placebo into the same clear size 0 capsules.  This 
repackaging is necessary to ensure that the physicians and the participants will be blinded during 
the study.  The capsules will be packaged in uniform airtight containers with 60 capsules per 
container. A third person not directly involved in care and assessment of the subjects, who also 
did the randomization, will be tasked to encode the capsules into groups A and B.  Bottles will be 
labelled with the corresponding patient number only.  Both the physician in charge and the 
patients will be unaware of which capsules contain Zinc Gluconate or placebo.  During the study, 
patients will be asked to draw a number from 1 to 32, and he/she will get the corresponding 
bottle.  The code will then be revealed during the data analysis portion to allow the statistician 
to segregate the results into the proper groups. 
 
Intervention 
Patients will be randomly assigned to 60 days of oral Zinc Gluconate capsules (one capsule 
of 200mg daily) versus the placebo capsules. The participants will be given a container filled with 
60 capsules.  They will be instructed to take 1 capsule once a day 20 minutes before the morning 
meal in their residence.  The starch placebos will be identical to zinc supplements in size, color, 
and shape hence both patients and investigators will be unable to tell whether participant will 
be on zinc supplementation or placebo.  
All participants will receive the same adapalene 0.3% + benzoyl peroxide 2.5% 
preparation to be applied two times a day on affected areas.  Patient education on Acne Vulgaris, 
Zinc sources, and basic skin care will be performed on all patients.  Instructions will be given to 
avoid intake of other medication or supplementation during the 60-day trial. 
 
Checking of Compliance  
 
Participants will be given a Daily Monitoring Sheet where they can note if they have taken 

the capsule for the day, as well as side effects or other remarks.  The number of remaining 
capsules will be checked every 2 weeks during follow-up. Patient will be required to bring 
medicine bottle on follow-up for the pill count. 
 
Final evaluation 
After 60 days of either placebo or zinc gluconate, the participant will be instructed to 
follow up for re-assessment.  The GAGS and acne inflammatory score will be re-evaluated.  The 
investigator will perform an examiner’s assessment score and the patient will also give a self-
assessment score. 
 
Outcome measures 
The primary outcome measure will be the change in inflammatory scores, GAGS scores of 
the zinc and placebo groups from initial consult to the end of the trial.  The secondary outcome 
measures include the examiner’s assessment score and the patient’s self-assessment score. 
 
Stopping Guidelines 
Criteria for stopping the intervention include anaphylactic reaction or allergies to the 
medications, and severe gastrointestinal symptoms.  Patients with severe adverse reactions will 
be treated accordingly to relieve symptoms.  They will be considered as “withdrawals” of the 
study, and still receive proper treatment for acne vulgaris. 
 
Dropouts and Withdrawals 
Withdrawals are defined as patients who discontinued the study for known reasons (did not 
comply with instructions, had severe adverse reactions).  Dropouts are defined as patients who 
cannot be contacted, had no more follow up, and whose outcomes are unknown by the end of 
the study period. 
 
 
Study Framework 

Figure 1. Study Framework 
 
 
Sample Size Computation 
The sample size is computed using G*Power software. The effect size used was based on 
“Low Doses of Zinc Gluconate for Inflammatory Acne” by Dreno, P et al. (1989). According to this, 
the inflammatory score was statistically lower in the Zinc group than in the Placebo group at 2nd 
month of observation with p-value less than 0.02. The computed effect size was 0.6708327, this 
was used given that there was no effect size convention available in G*Power for repeated 
measures between factors (ANOVA, F-test). The computed sample size of 12 (6 per group) was 
estimated using 0.05 α-level of significance at 80% actual power of analysis.  Twenty percent of 
the computed sample size was added to adjust for the dropout rate. Thus, the minimum required 
sample size is 15.  The sample sizes for power of analysis are shown in Table I. 
 
Power of 
Analysis 
Sample 
Size 
Group 
1 
Group 
2 
99% 
24 
12 
12 
95% 
18 
9 
9 
90% 
16 
8 
8 
80% 
12 
6 
6 
Table I. Sample sizes for power of analysis 
 
Statistical analysis plan 
For the profiling of patients, quantitative variables (e.g. age, inflammatory scores, and 
GAGS scores) will be summarized using the mean and standard deviation or median and range 
(Min-max) if the data appears scattered. Meanwhile, qualitative variables (e.g. sex, examiner’s 
assessment, patient’s self-assessment) will be described as frequencies and percentages. The 
point and 95% confidence interval estimate of the mean inflammatory scores and GAGS scores 
Diagnosed 
Acne Vulgaris 
patients
Oral Zinc 
Gluconate 
group
INITIAL VISIT: 
GAGS, 
inflammatory 
score
MONTH 1: 
GAGS, 
Inflammatory 
score
MONTH 2: 
GAGS, Inflammatory 
score. Examiner's 
assessment, Patient's 
assessment
Placebo 
group
INITIAL VISIT: 
GAGS, 
inflammatory 
score
MONTH 1: 
GAGS, 
Inflammatory 
score
MONTH 2:
GAGS, Inflammatory 
score. Examiner's 
assessment, Patient's 
assessment

of the two treatment groups will be measured at baseline, at one month, and at the end of the 
trial. Lastly, independent two-sample t-test will be used to compare the two treatment groups in 
terms of: 1) the mean change in the inflammatory scores from baseline to end of the trial; 2) the 
mean change in the GAGS scores from baseline to end of the trial. Alternatively, Mann-Whitney 
U-Test will be used as an alternative if the data will be dispersed. Repeated measures ANOVA will 
be used to compare the inflammatory score and GAGS score of acne vulgaris patients on initial 
consult, at 4 weeks, and at 8 weeks. Friedman test will be used as a non-parametric alternative.  
A 5% level of significance will be used in this hypothesis testing. SPSS version 25.0 will be 
used for all output and the necessary descriptive and inferential statistics in this study. 
 
DUMMY TABLES 
Table 2. Demographic profile of patients 
  
Zinc Gluconate (n=  ) 
Placebo (n=  ) 
 
Mean 
SD 
Mean 
SD 
Age in years 
 
 
 
Frequency 
Percentage 
Frequency Percentage 
Sex 
 
 
     Male 
 
  
     Female 
  
  
 
Table 3. Mean Inflammatory Scores 
Mean Inflammatory Scores 
Period 
Zinc Gluconate (n=  ) 
Placebo (n=  ) 
  
Mean 
SD 
Mean 
SD 
Initial 
  
  
  
  
Month 1 
  
  
  
  
Month 2 
  
  
  
  
 
Table 4. Mean GAGS Scores 
Mean GAGS Scores 
Period 
Zinc Gluconate (n=  ) 
Placebo (n=  ) 
  
Mean 
SD 
Mean 
SD 
Initial 
  
  
  
  
Month 1 
  
  
  
  
Month 2 
  
  
  
  
 
Table 5. Comparison of two treatment groups in terms of mean change in the inflammatory 
scores and GAGS scores from baseline to end of the trial 
Mean change of outcomes from baseline to end of the trial 
Outcomes 
Zinc Gluconate (n= ) 
Placebo (n=  ) 
p value 
 
Mean 
SD 
Mean 
SD 
 

Inflammatory Score 
  
  
  
GAGS score 
  
  
  
 
Table 6. Frequency of each category for examiner's assessment 
Examiner's Assessment of Improvement of Acne 
Assessment 
Zinc Gluconate (n=  ) 
Placebo (n=  ) 
  
Frequency 
Percentage 
Frequency 
Percentage 
No Improvement 
  
  
  
  
Slight Improvement (<50%) 
  
  
  
  
Marked Improvement (≥50%) 
  
  
  
  
 
Table 7. Frequency of each category for patient’s self-assessment 
Patient's Self-Assessment of Improvement of Acne 
Assessment 
Zinc Gluconate (n=  ) 
Placebo (n=  ) 
  
Frequency 
Percentage 
Frequency 
Percentage 
No Improvement 
  
  
  
  
Slight Improvement (<50%) 
  
  
  
  
Marked Improvement (≥50%) 
  
  
  
  
 
 
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