Chapter 4. Results: Evidence

	This chapter summarizes the evidence collected. A summary of evidence is presented first, followed by separate discussions of the evidence for each treatment class.  Most outcomes relate

to therapeutic efficacy.  Psychological and compliance outcomes are discussed at the end of the

chapter. 

	We have detailed the evidence into seven types of evidence tables.  A summary table lists

overall information about every trial included in our synthesis. All two- and three-arm trials are

summarized in a heading table, a continuous outcomes table, and a discrete outcomes table.

Trials with more than three arms have their results summarized in the multi-arm heading table,

multi-arm continuous outcomes table, and multi-arm discrete outcomes table.  These tables may

be found in Volume 2 of this evidence report, along with a comprehensive index to the evidence

tables and a detailed description of the format and contents of each table type. 

Summary of Evidence

Overview 

	The evidence syntheses on the following pages qualitatively evaluate and integrate findings from the trials. The approach was to focus on pairwise comparisons of treatment (a target and a

comparator), even when three or more arms were involved in the trial. The comparisons are

organized by treatment classes. Within each treatment class (denoted by letters A through N), are

sets of comparisons pertaining to a single treatment (e.g., isotretinoin [topical] is E.02, where E

refers to the treatment class of topical retinoids). These sets are ordered alphabetically, by the

name of the target treatment. Finally, within each set are comparisons of like targets and

comparators. These comparisons are sequenced by the treatment class of the comparator. Thus,

treatment vs. inert comes first (e.g., E.02.01, isotretinoin [topical] vs. inert [topical]), treatment vs. keratolytic comes next (e.g., E.02.02, isotretinoin 0.1 percent [topical] vs. benzoyl peroxide [topical]), etc. To review a description of a treatment, see Table 11. Because we could not be

certain of finding all brand names for all generic treatments, we have included no brand names,

except when needed to distinguish two particular therapies within the same trial.

	Our qualitative syntheses have three components. We first describe the trials in the

comparison, highlighting from the evidence tables those features important in making our final

assessment. For instance, we highlight methodological concerns that influence the assessment of

the quality of the evidence. Note that these descriptions may include data from our review that

are not presented in the evidence tables, due to space limitations, like funding relationships with  pharmaceutical companies. We do not include instances in which it is reported that a 

pharmaceutical company funded a trial because half of the trials did not report source of funding. 

However, we do include instances in which a pharmaceutical employee is listed as an author or

co-author of a study article because editors quite consistently indicate author affiliation.

	Investigators used the term “effective” to cover a range of outcomes. We collected outcomes

into three categories: subjective assessment overall (by patient or physician); assessment of severity on observed attributes only (e.g., Leeds score); and lesion count.  We call a result in any

category as “effective” if the trial demonstrated a statistically significant difference between

arms, and we assign the highest assessment of evidence to difference that took baseline values

into account (e.g., percent change of lesion counts).

	Finally, we summarize the evidence in a table, indicating the direction of the relative

effectiveness (> or =), the context of comparison (acne type or severity, if available), and an

assessment of the strength of the evidence (levels A, B, and C).

	Several criteria are used to determine into what category a given body of evidence lies. Trial

quality, trial size, the size of the observed effect, the statistical evidence for effect (i.e., P-values

and confidence intervals), and the number of trials all had weight in the summary judgment. In

general, the minimum standard for “Level A” evidence is at least two trials of acceptable quality

showing moderate to strong statistical evidence for a clinically meaningful endpoint and effect.

“Level B” evidence is evidence of modest strength, which can occur when only one trial

addresses a comparison, when several trials have somewhat different qualitative conclusions,

when there are large differences that fall short of statistical significance, or when poor trial

quality prevents accepting strong statistical evidence at face value. “Level C” evidence is

evidence that does not permit coming to any scientific conclusion, either because of a paucity of

evidence, conflicting evidence, or very poor quality evidence. 

Details

	Descriptions of the trials focus on a number of features. The following are the default features that we do not comment on:

•	Parallel design

•	Mixed gender

•	Mixed ages (adolescent through adult)

	Unless stated otherwise, the trials in the comparisons have these features or do not provide

data in age or gender. The remainder of this section describes the features that we do describe.

	We categorize sample size as very small (arm size less than 10), small (arm size less than 25), medium (25 to 50), and large (greater than 50). These distinctions are based on the t-test, the core statistical test in two-arm comparisons, and the one used most often in the trials under review

here. In a two-sample t-test, 25 subjects in each arm usually suffices to detect a one-standard- deviation difference between groups. For instance, Cunliffe calculated a sample size of 65-75

patients per arm to detect a 15 percent relative difference, so smaller trials may not have enough

statistical power to detect desired differences.26 For cross-over and split-face trials, the effective sample size is doubled, because of the increased power from using patients as their own control.

Thus, a cross-over trial with 30 patients in each arm is like a two-sample trial with 60 patients in

each arm, and we categorize those as large. On the other hand, as the number of arms goes up in a trial, the number of patients in an arm is smaller: A three-arm trial with 120 patients is medium.

	The adequacy of sample size depends on the conclusion being sought. The designations in the previous paragraph apply to outcomes that demonstrate a difference. A larger sample size is

necessary when drawing conclusions about equivalence. Hence, while we may conclude that sample size is sufficient to lead to a conclusion that one treatment is better than another, we will

conclude that the sample size may only lead us to a Level B assessment of the evidence that two

treatments are equivalent. Finally, because side effect rates are generally low, and because

inference of low-rate events is sensitive to the numerator, we often assess the evidence regarding

side effects as Level B or C.

	We categorize ages in parallel to the stratification used by the Centers for Disease Control

and Prevention: early adolescent, 10-15 years old; late adolescent, 15-19 years old; young adult,

20-24 years old. 

	Acne severity is discussed more fully in Chapter 3. If we were unable to assign a baseline

acne severity category to a trial (i.e., “can’t say” in the evidence tables), we will say that “acne

severity could not be categorized” or something similar.

	Table 13 presents a summary of evidence for effectiveness.  In the column showing the number of subjects (N), we provide a total by adding together the total sample sizes of every study included in each comparison. Although ideally, we should include patients included only in

the relevant arms, this proved difficult to do consistently because of consistency among authors 

and because some studies contributed fewer than all their arms to the comparison. The estimated

numbers are, therefore, overestimates. The intention of our totals is to provide a sense of the

precision of the evidence, rather than to be exact on the number of subjects providing evidence.

The reader is directed to the specific evidence tables in Volume 2 for exact details. 

	Table 14 provides a summary of evidence regarding side effects. Many of the treatments

reviewed here have side effects that are well known and included in package inserts. The reader

is referred there for more complete listings.  We report here only those side effects reported in the

trials reviewed.

Class A.	Cleansers

A.01.01   –	Acidic Syndet Bar (topical) vs. Soap

	There is one medium trial, Trial 197,27 of late adolescents and young adults with mild acne. Although patients were not blinded, the trial was randomized and the enroller was blinded. Both

cleansers statistically significantly reduced the count of inflammatory lesions, but there was no

statistical difference between the two. The effect on non-inflammatory lesions was not

statistically significant. The syndet bar resulted in statistically significantly fewer side effects

(itching, redness, scaling).

A.01.015   –	Aluminum Oxide (topical) vs. Other Cleansers (topical)

	There was one small five-arm trial, Trial 23928 that studied the cleansers or abradants aluminum oxide, polystyrene, polyethylene, polyester, and pumice in patients with moderate to

severe acne. Patients were not randomized, physicians were not blinded, there were no losses to

followup, and the arms were not comparable. Outcomes focused on non-inflammatory lesions;

differences were not statistically significant.

A.01.02   –	Hexachlorophene (topical) vs. Triclosan (topical)

	See C.09.02.

A.01.03   –	Polyprepolymer-2 (topical) vs. Tretinoin (topical)

	See E.05.01.

A.01.04   –	Povidone-iodine (topical) vs. Vehicle

	There was one small trial, Trial 235,29 of mildly affected patients for which treatment details are not provided and there were major losses to followup. No comparison statistics are provided.

There was a single case of itching in the vehicle group.

A.01.05   –	Silicic Acid (topical) vs. Inert

	There was one medium trial, Trial 204,30 of subjects with moderate acne. Although silicic acid produced greater reductions in lesion counts relative to vehicle, these differences were not

statistically significant. No data about side effects were reported.

A.01.06   –	Soybean Liposome/Glycolic Acid (topical) vs. Soybean Liposome (topical)

	See B.07.06.

Class B.	Keratolytic (topical)

B.01	   –	Azelaic Acid (topical) 

B.01.01  –	Azelaic Acid (topical) vs. Inert (topical)

There were two trials: one small British trial, Trial 77,31 and one medium Greek trial, Trial 187.32 The Greek trial studied subjects with moderate acne; the British trial matched subjects, but the acne severity cannot be categorized. Both trials were randomized and measured changes in

inflammatory and non-inflammatory lesions.

Both trials showed statistically significant reductions in inflammatory and non-inflammatory

lesions at 2-3 months in subjects treated with azelaic acid. Trial 187 also showed a significant

improvement in physician rating of overall change.

Side effects, including burning, erythema, itching, and scaling were reported in small

numbers in both treatment and placebo groups.

B.01.02   –	Azelaic Acid (topical) vs. Benzoyl Peroxide (topical)

There was one large (N = 309) trial, Trial 52.33 Limited information about the subjects and methodology was provided. Although significant changes from baseline were reported in both treatment groups, neither treatment was superior in the short-, medium-, or long-term (maximum

followup = 24 weeks). No between-group P-values were reported. The authors reported that

benzoyl peroxide produced a more rapid effect. 

No specific information about side effects was reported, although the authors stated that

azelaic acid applications were “better tolerated.”

B.01.03   –	Azelaic Acid (topical) vs. Tretinoin (topical)

See E.05.04.

B.01.04   –	Azelaic acid (topical) vs tetracycline (oral) 

See H.08.05.

B.02     –	Azelaic Acid/Glycolic Acid (topical)

B.02.01   –	Azelaic Acid/Glycolic Acid (topical) vs. Tretinoin/Vehicle (topical)

See E.05.04.

B.03	   –	Salicylic Acid (topical)

B.03.01   –	Salicylic Acid (topical) vs. Inert

There were two trials, a large matched-control trial of 114 patients, Trial 95,34 of 2 percent salicylic acid and a medium parallel trial, Trial 294,35 of 1.5 percent salicylic acid. Trial 95 had serious methodological flaws as almost half the subjects departed from protocol at some point

secondary to side effects. 

Both trials reported greater improvements from baseline in the group treated with salicylic

acid. In the matched-control trial, these differences were statistically significant at 12 weeks but

not at 4 weeks. In Trial 294, salicylic acid led to an apparently greater improvement in facial

oiliness, but comparison statistics were not provided.

The parallel trial reported local reactions (skin and eye burning) in 10 subjects in the salicylic

acid group and none in the placebo group. No P-values were provided. No side effects data were

reported in the large trial.

B.03.02   –	Salicylic Acid (topical) vs. Benzoyl Peroxide (topical)

See D.01.04.

B.04     –	Sulfur/Resorcinol (topical)

B.04.01   –	Sulfur/resorcinol (topical) vs. benzoyl peroxide (topical)

See D.01.05.

B.04.015  –	Sulfur/Resorcinol/Salicylate (topical) vs. Tretinoin (topical)

See E.05.015.

B.04.02   –	Sulfur/Resorcinol (topical) vs. Vitamin A (topical)

See E.06.02.

B.05     – 	Sulfur (topical)

B.05.01   – 	Polythionate/Quaternary Ammonia Complex of Polythionate (topical) vs. Polythionate (topical) 

There was one medium trial, Trial 86,36 where acne severity could not be categorized. Although treatment duration was not specified, data were given at 1 year, at which time overall

change was comparable between the two groups. The authors reported that there were no side

effects.

B.05.02   –  	Sulfurated Lime (topical) vs. Vehicle (vehicle)

There was one medium trial, Trial 101,37 of patients with moderate acne. The single efficacy outcome, subjectively assigned severity change, was statistically significantly better in the

treatment group, with two-thirds moderately or excellently improved versus one-quarter in the vehicle group. No side effects data were reported.

B.06     – 	Sulfur/Salicylic Acid/Resorcinol (topical)

B.06.01   –   	Komed® (Sulfur/Salicylic Acid/Resorcinol) (topical) vs. Inert

There was one large (N=51) split-face trial, Trial 191,38 of subjects with mild, moderate, and severe acne. Subjects were a referral population and there were no reported losses to followup.

The one outcome was physicians’ assessment of superiority of one face-side versus the other. Komed®  was rated as better on both sides of the face, although comparison statistics were not provided. No data about side effects were reported.

B.06.02   –	Komed® (Sulfur/Salicylic Acid/Resorcinol) (topical) vs. Proprietary Formula (Sulfur/Salicylic Acid/Resorcinol) (topical)

There was one large (N=51) split-face trial, Trial 191,38 of subjects with mild, moderate, and severe acne. Subjects were a referral population and there were no reported losses to followup.

Treatment was administered for 16 weeks, with followup for up to 36 weeks. The outcome

measured was overall change in acne by physician assessment. The one outcome was physicians’ assessment of superiority of one face-side versus the other. Komed® was rated as about the same as the proprietary formula, although the numbers are small. No data about side effects were

reported.

B.07     – 	Other Keratolytics

B.07.01   –	Aluminum Chloride (topical) vs. Vehicle

There was one small split-face trial, Trial 165,39 of patients with mild to moderate acne. Reported data show that patients were blinded. The single outcome, assessment of overall

change, was not statistically significantly different. No side effect data were reported.

B.07.02   –	Aluminum Chlorhydroxide/Sulfur (topical) vs. Inert

There was one large (N = 776) multi-center trial, Trial 228.40 The trial was conducted at multiple sites in the United Kingdom and represents pooled data from multiple trials conducted

in general practices and dermatologists’ offices without specific information about how these

data were combined. Characteristics of the subjects and specific methodological information

were not reported. No specific information about blinding of subjects or assessors was reported.

At 5 weeks, 142 of 201 subjects treated with aluminum chlorhydroxide/sulfur were improved, by

physician assessment of overall change in acne, compared to 76 of 151 treated with vehicle

alone. This was statistically significant at p<0.001. No information about side effects was

reported.

B.07.03   –	Aluminum Chlorhydroxide/Sulfur (topical) vs. Neomycin/Methylprednisolone 

	See N.02.06.

B.07.04   –	Gluconolactone (topical) vs. Inert

There was one large (N = 150) trial, Trial 176,41 of patients with moderate to severe acne. Although subjects in the two groups were reportedly similar in terms of acne duration at

enrollment, no data were provided to support this. Although acne severity was assessed at

baseline, it was not clear that the groups were comparable. From the lesion count data provided,

gluconolactone led to a statistically significant decrease in inflammatory and total lesion counts,

with respect to baseline, although only the change in inflammatory lesions was statistically

significantly better than the change in subjects treated with placebo. Side effects reported were

dryness, scaling, burning, stinging, and redness. These effects were more frequently reported in

the gluconolactone group. No P-values were reported.

B.07.05   –	Gluconolactone (topical) vs. Benzoyl Peroxide (topical) 

	See D.01.03.

B.07.06   –	Soybean Liposome/Glycolic Acid (topical) vs. Soybean Liposome (topical)

	There was one small split-face, multi-center trial, Trial 246,42 of mild-to-moderately affected patients, notable for no losses to followup, and for a pharmaceutical-employee co-author. Both

treatments were effective on comedones, papules, and pustules, with the combined treatment

being statistically significantly better in each lesion type. There were more withdrawals from the

combination group, but the number (2) was small.

B.07.07   –	Nicotinamide (topical) vs. Clindamycin (topical)

	See C.01.02.

Class C.	Anti-bacterial (topical)

C.01     –	Clindamycin (topical) 

C.01.01   –	Clindamycin (topical) vs. Inert

	There were eight trials addressing the effectiveness of topical clindamycin preparations

(clindamycin phosphate or clindamycin hydrochloride) versus inert substances (placebos or

vehicles): four large (Trial 20,43 Trial 33,44 Trial 99,45 and Trial 21446), two medium (Trial 199,47 Trial 217,48), and two small (Trial 32749 and Trial 14450). These trials included subjects with mild to severe acne and an approximate mean age of 20 years. Seven of the trials were conducted in

the USA and one (Trial 33) was conducted in Oslo, Norway. Four trials studied a dose of 1

percent applied twice daily, one studied a dose of 1 percent before bed, and three reported no

dose information. 

	Subjects treated with clindamycin had similar reductions in lesion counts to those treated

with inactive substances. Clindamycin tended to produce greater reductions in inflammatory

lesions and greater reductions when counts were assessed at later time points, but these results

were rarely statistically significant. Clindamycin was more consistently superior to placebo when

global measures of acne severity or improvement were measured by subject or physician report.

There were limited data reported regarding side effects. These data tended to show similar rates

of cutaneous side effects and diarrhea between subjects treated with clindamycin and inactive

preparations, although insufficient data were reported for statistical significance. There was one

case (Trial 20) of diarrhea attributed to clindamycin; the patient was withdrawn, and it was not

pseudomembranous colitis. One patient, in Trial 20, dropped out because of local burning.

C.01.02   –	Clindamycin (topical) vs. Nicotinamide (topical)

	There was one medium multi-center trial, Trial 305,51 of patients with moderate acne. The trial was compromised by major losses to followup. While both preparations produced

improvement in severity and lesion counts, there were no statistically significant differences between them for any of the outcomes measured. There were no reported differences in local

reactions between the two treatments.

C.01.03   –	Clindamycin (topical) vs. Clindamycin (topical)

	There were six parallel trials that reported on the relative effectiveness of different topical

clindamycin preparations. Three trials (Trial 2043 Trial 143,52 Trial 22953) tested clindamycin phosphate versus clindamycin hydrochloride. Four trials (Trial 99,45 Trial 131,54 Trial 229,53 Trial 26755) tested clindamycin in different vehicles such as gel, lotion, and solution. All were parallel trials of subjects with acne severity ranging from mild to severe. Two of the trials (Trial 143,

Trial 229) used a split-face design.

	Trials of topical clindamycin phosphate versus topical clindamycin hydrochloride showed no

significant differences in severity or lesion counts between the two preparations.

Trials of topical clindamycin in different vehicles failed to show differences in effectiveness

whether the vehicle was a gel, lotion, or solution. Trial 229 showed slightly greater improvement

with the Ionax® preparation versus the E-Solve® preparation.

	There were no significant differences in side effects between various topical clindamycin

preparations. Trial 131 showed slightly less drying and erythema associated with use of lotion 

versus solution. Across the trials, there were two cases of mild diarrhea that did not lead to

discontinuation of treatment.

C.01.04   –	Clindamycin (topical) vs. Erythromycin (topical)

	There were five parallel trials involving subjects that compared topical preparations of

clindamycin to topical preparations of erythromycin. There were four large trials, Trial 15856 (120 patients), Trial 20857 (109 patients), Trial 24458 (120 patients), and Trial 30359 (178 patients). There was one medium trial, Trial 326.60  These trials generally compared 1 percent clindamycin to 2 percent erythromycin, although one trial (Trial 32660) used 1.5 percent clindamycin and 2 trials (Trial 303,59 Trial 32660) used 1.5 percent erythromycin. All the trials enrolled subjects with mild to severe acne. Trial 158 had blinded ascertainment, but neither physicians nor patients

were blinded. In Trial 208, patients were not blinded. Trial 244 had no losses to followup, but the

enroller was not blinded, and arms were not comparable.

	Although several trials documented differences between the preparations for certain

outcomes at certain time points, these differences occurred in favor of each treatment within

individual trials and none of the trials showed consistent differences overall. A review of all five

trials fails to show that one treatment is superior to the other.

	There was very limited information on side effects reported in these trials.

C.01.05   –	Clindamycin (topical) vs. Tetracycline (topical)

	There were two parallel trials that compared the effectiveness of topical clindamycin (1

percent twice daily to topical tetracycline (no dose specified in either trial). One medium trial, Trial 26161 included patients with mild to moderate acne, the other medium trial was of patients with mild acne, Trial 291.62

	Although differences in specific lesion counts or changes in lesion counts were insignificant

or inconsistent, both trials showed a significant difference in favor of clindamycin in their overall

measures of acne severity or improvement. In Trial 261, overall improvement was rated as

“poor” in 2 of 22 in the clindamycin group and 13 of 27 in the tetracycline group. In Trial 291,

acne severity at 8 weeks was rated as poor in 1 of 44 in the clindamycin group and 11 of 43 in the

tetracycline group.

	There were no differences in side effects in either trial, although information was limited.

C.01.06    –	Clindamycin (topical) vs. Benzoyl Peroxide (topical)

	There was one large multi-center, multi-arm trial, Trial 214,46 and two small trials, Trial 32463 and Trial 329,64 of patients with moderate acne. All three trials used 1 percent clindamycin and 5 percent benzoyl peroxide. Trial 324 and Trial 329 studied twice daily application and Trial 214

studied before-bed application. 

	All three trials demonstrated significant reductions in inflammatory and non-inflammatory

lesions from baseline for both treatments. There was no statistically significant difference

between the two at any time point except at 12 weeks in Trial 324 when a significantly greater

reduction in non-inflammatory lesions was noted in the benzoyl peroxide group. Similarly, in

Trial 329, benzoyl peroxide led to a statistically significantly greater reduction in severity, with

respect to baseline, than did clindamycin, at 10 weeks.

	Except for statistically significantly greater irritancy score for benzoyl peroxide in Trial 329,

data about side effects in these trials did not support a statistically significant difference in local

reactions such as erythema, peeling, dryness, burning, pruritus, or oiliness.

C.01.07   –	Clindamycin (topical) vs. Clindamycin/Benzoyl Peroxide (topical)

	There was one large (N=393) parallel, multi-center, multi-arm trial, Trial 214,46 that reported on the relative effectiveness of topical clindamycin (1 percent) versus topical clindamycin (1

percent)/benzoyl peroxide (5 percent) applied before-bed for treatment of moderate acne. Both

preparations produced significant reductions from baseline of inflammatory and non-

inflammatory lesions. These reductions were greater for the combination of clindamycin/benzoyl

peroxide than for clindamycin alone. More subjects had their acne rated as good or excellent in

the combination group relative to the clindamycin alone group. 

	Side effects reported were erythema, peeling, burning, dryness, and pruritus. Peeling was

reported relatively more often in subjects using the clindamycin/benzoyl peroxide preparation.

C.01.08   –	Clindamycin (topical) vs. Erythromycin/Benzoyl Peroxide (topical) 

	See D.05.02.

C.01.09   –	Clindamycin (topical) vs. Erythromycin/Zinc (topical)

	See N.08.03.

C.01.10   –	Clindamycin (topical) vs. Tretinoin/Clindamycin (topical)

	See G.02.01.

C.02    –	Clindamycin/Benzoyl Peroxide (topical)

C.02.01   –	Clindamycin/Benzoyl Peroxide (topical) vs. Inert

	See D.04.01.

C.02.02   –	Clindamycin/Benzoyl Peroxide (topical) vs. Clindamycin (topical)

	See C.01.07.

C.02.03   –	Clindamycin/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	There was one large parallel multi-center, multi-arm trial, Trial 214,46 and one medium trial, Trial 329,64 of patients with moderate acne. In Trial 214, the combination produced statistically significantly greater reductions from baseline of inflammatory and non-inflammatory lesions than

benzoyl peroxide alone. However, in Trial 329, the number of lesions appeared comparable (no

P-values were provided), and severity was improved to a statistically significant extent with

respect to clindamycin, not with respect to benzoyl peroxide. A larger proportion of subjects had

their acne rated as good or excellent in the combination group. Side effects reported with

relatively equal frequency in both groups were erythema, peeling, burning, dryness, and pruritus.

C.03     –	Erythromycin (topical)

C.03.01   –	Erythromycin (topical) vs. Inert

	There were four large parallel trials (Trial 184,65  Trial 205,66 Trial 274,67 and Trial 8968), two medium trials (Trial 27769 and Trial 3970), and two small studies (Trial 15771 and Trial 28572) of patients with mild to moderate acne. 

	Six trials showed statistically significant improvement in inflammatory lesions by

erythromycin. Trial 157 reported that more patients treated with erythromycin assessed their acne

as “better” than did those treated with vehicle, but P-values were not provided. Trial 277 failed to

show a difference between the preparations in terms of inter-treatment lesion change at 8 weeks.

	There were no reported differences in side effects between topical erythromycin and its

vehicle.

C.03.02    –	Erythromycin (topical) vs. Clindamycin (topical):

	See C.01.04.

C.03.025  –	Erythromycin (topical) vs. Benzoyl Peroxide (topical)

	There was one medium, three-arm trial, Trial 39,73 comparing erythromycin 1.5 percent twice daily, against benzoyl peroxide 5 percent twice daily. Patients were not randomized. Severity and

lesion count changes were comparable in the two arms. One patient withdrew from each arm

because of dermatitis.

C.03.03    –	Erythromycin (topical) vs. Erythromycin/Zinc (topical)

	See N.08.02.

C.04     –	Fusidic Acid (topical)

C.04.01   –	Fusidic Acid (topical) vs. Inert

	There were two medium trials, Trial 15174 and Trial 315,75 of patients with mild to moderate or non-categorizable. No statistically significant differences between topical fusidic acid and

inactive preparations were observed.

C.04.02   –	Fusidic Acid (topical) vs. Doxycycline (oral) 

	See H.03.02.

C.04.03   –	Fusidic Acid (topical) vs. Sodium Fusidate (oral)

	See H.09.04.

C.05     –	Meclocycline (topical)

C.05.005  –	Meclocycline (topical) vs. Inert (topical)

	There were two large two-arm trials, Trial 19476and Trial 195,76 of patients with moderate to severe acne. Both trials had no losses to followup, but no randomization and inconsistent

ascertainment across arms. There was a statistically significantly greater decrease in

inflammatory lesions at 5 and 11 weeks in the meclocycline group. The side effect of follicular

staining was noted in about 16 percent of anti-bacterial-treated patients, but none in the vehicle

group.

C.05.01   –	Meclocycline (topical) vs. Benzoyl Peroxide (topical)

	There was one large (N=102) trial, Trial 30,77 of young adults with moderate acne. There were no losses to followup, but the outcome assessor was not blinded. Comedone count was

statistically significantly fewer in the benzoyl peroxide group, but not for papules and pustules.

There were three cases of skin discoloration split between both groups.

C.05.02   –	Meclocycline (topical) vs. Meclocycline/Benzoyl Peroxide (topical)

	See D.06.01.

C.05.03   – 	Meclocycline (topical) vs. Tetracycline (oral)

	See H.08.06.

C.06     –	Metronidazole (topical)

C.06.01   –	Metronidazole (topical) vs. Inert

	There was one medium trial, Trial 328,78 of patients with mild to moderate acne. No significant differences between topical metronidazole and placebo were observed in this trial.

C.07     –	Neomycin (topical)

C.07.01   –	Neomycin (topical) vs. Keratolytics/Anti-inflammatory (topical)

	There was one medium multi-arm trial, Trial 287,79 with patients whose acne status cannot be categorized, whose reported execution differed from the reported design. The following

proportions of subjects were classified as improved in each group: neomycin, 10 of 20; vehicle,

14 of 26; hydrocortisone, 14 of 24; sulfur, 11 of 23; resorcinol, 17 of 24; combination, 21 of 32.

Differences were not statistically significant.

C.08	  –		Tetracycline (topical)

C.08.01   –	Tetracycline (topical) vs. Inert

	There were four large parallel trials: Trial 1080 (moderate severity), Trial 2381 (moderate), Trial 4082 (cannot determine severity), and Trial 31383 (mild to moderate severity). The first three used topical tetracycline 0.5 percent twice daily. The fourth trial used topical tetracycline 2.2

percent twice daily. 

	The three trials using 0.5 percent reported no statistically significant differences between

topical tetracycline and inactive preparations. In the fourth trial, 25 patients treated with

tetracycline were classified as “better” compared to 18 in the placebo group.

	In the trial using 2.2 percent, tetracycline was associated with more skin discoloration,

placebo with more exfoliation.

C.08.02    –	Tetracycline (topical) vs. Clindamycin (topical) 

	See C.01.05.

C.08.03    –	Tetracycline (topical) vs. Benzoyl Peroxide (topical)

	There was one large (N=69, 45 females, age range 12-33 years) parallel trial, Trial 255,84 comparing the effectiveness of topical tetracycline to topical 5 percent benzoyl peroxide applied

once per day for treatment of moderate acne. Outcomes assessed at 8 and 12 weeks were acne

severity (by the Leeds method) on back, face, and chest as well as counts of inflammatory and

non-inflammatory lesions.

	No significant differences were observed between topical tetracycline and topical benzoyl

peroxide in any of the outcomes assessed.

C.08.04    –	Tetracycline (topical) vs. Povidone-Iodine/Tetracycline (topical) 

	See H.08.14.

C.08.05    –	Tetracycline (topical) vs. Oxytetracycline (oral) 

	See H.06.05.

C.08.06    –	Tetracycline (topical) vs. Tetracycline (oral)

	See H.08.04.

C.09    –		Triclosan (topical)

C.09.01   –	Triclosan (topical) vs. Inert

	There was one medium trial, Trial 114,82 of patients with mild to moderate acne. The trial was conducted using male subjects at a military hospital.

	No significant differences were observed between topical triclosan and placebo in any of the

outcomes assessed (patients’ assessment of change and lesion counts). No side effect data were

reported.

C.09.02    –	Triclosan (topical) vs. Hexachlorophene (topical)

	There was one medium cross-over trial, Trial 2185 (N=34). The trial reported the involvement of a pharmaceutical company. Outcomes assessed at 6 and 12 weeks were overall change as

assessed by the subjects and by a physician.

	There were no significant differences reported for either of the outcomes (patients’

assessment of change and lesion counts) between topical triclosan and topical hexachlorophene.

Almost all patients in both arms experienced local drying, scaling, or itching.

C.09.03    –	Triclosan/propylene Phenoxetol (topical) vs. Vehicle vs. Triclosan

	There was one medium trial, Trial 40,82 of patients with mild to moderate acne. The trial was conducted using male subjects at a military hospital. No significant differences were observed between topical triclosan and a topical preparation of triclosan and propylene phenoxetol in any

of the outcomes assessed (patients’ assessment of change and lesion counts). No side effect data

were reported.

Class D.	Anti-bacterial (topical)/Keratolytic (topical) Combinations

D.01      –		Benzoyl Peroxide (topical)

D.01.01   –	Benzoyl Peroxide (topical) vs. Inert

	There were seven parallel trials. Trial 24186, Trial 173,87 and Trial 31488  were medium, two- arm trials; Trial 17641 was a medium, three-arm trial; Trial 17789 and Trial 9790 were medium, four-arm studies, and Trial 21446 was a large, four-arm trial. Each studied the 5 percent concentration of benzoyl peroxide, except for Trial 314, which used 20 percent. Two of these

(Trial 173, Trial 314) were specifically designed for this comparison. In each of the others,

benzoyl peroxide was used as the control treatment for other active preparations. The trials were

conducted in Britain (Trial 173, Trial 177), Australia (Trial 176), and the USA (Trial 214, Trial

241). Four of the trials studied twice daily application of the treatment (Trial 173, Trial 177, Trial

241, and Trial 314), one studied before-bed application (Trial 214), one (Trial 97) had patients

applying treatment between once and four times daily, and the other gave no details about how

the treatment was used. Acne severity ranged from mild to severe in the trials.

	All trials showed improvements from baseline in their measures of acne severity. These

changes were consistently superior to the effects of placebo at a statistically significant level.

	Side effects such as erythema, peeling, dryness, burning, pruritus, stinging, itching, and

soreness were reported more frequently in groups treated with benzoyl peroxide. In Trial 176, of

moderately-to-severely affected patients, local side effects were statistically more frequent than

in the vehicle group.

D.01.02   –	Benzoyl Peroxide (topical) vs. Azelaic Acid (topical)

	See B.01.02.

D01.03    –	Benzoyl Peroxide (topical) vs. Gluconolactone (topical)

	There was one large trial, Trial 176,41 of patients with moderate to severe acne. Although subjects in the two groups were reportedly similar in terms of acne duration at enrollment, no

data were provided to support this. Although acne severity was assessed at baseline, it was not

clear that the groups were comparable. The decrease was statistically significantly greater in

benzoyl peroxide for inflammatory and non-inflammatory lesions. Side effects reported were

dryness, scaling, burning, stinging, and redness. These effects were less frequently reported in the

gluconolactone group. No P-values were reported.

D.01.04   –	Benzoyl Peroxide (topical) vs. Salicylic Acid (topical)

	There was one medium cross-over trial, Trial 304,91 of mild acne. There were no losses to followup or important protocol departures reported. However, the subjects, enrollers, and

outcomes assessors were not blinded to treatment assignment. There were no statistically

significant differences in change in comedones between the preparations in either phase of the

trial. Information regarding side effects was not reported.

D.01.05   –	Benzoyl Peroxide (topical) vs. Sulfur/Resorcinol (topical)

	There was one large (N = 189) trial, Trial 272,92 where acne severity could not be categorized. There was very limited information about methodology reported. A greater

reduction in total lesions was observed in the benzoyl peroxide group versus the sulfur/resorcinol

group, but this difference was not statistically significant. No data about side effects were

reported.

D.01.06   –	Benzoyl Peroxide (topical) vs. Clindamycin Phosphate (topical) 

	See C.01.06.

D.01.07   –	Benzoyl Peroxide (topical) vs. Meclocycline (topical)

	See C.05.01.

D.01.08   –	Benzoyl Peroxide (topical) vs. Tetracycline (topical)

	See C.08.03.

D.01.09 –	Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	There were seven trials that compared various preparations of topical benzoyl peroxide to one

another. These comparisons were drawn between benzoyl peroxide in different vehicles (alcohol,

water, acetone, gel, lotion) and different concentrations (2.5 percent, 5 percent, and 10 percent).

	Trial 35193 was a large two-arm trial comparing 2.5 percent with a 5 percent preparation. There were no losses to followup, but physicians were not blinded. Trial 24286 was a medium trial of patients with mild to moderate acne that compared the effectiveness of topical benzoyl

peroxide (2.5 percent) and topical benzoyl peroxide (5 percent) applied twice daily. There were

no reported losses to followup. Trial 24386 was a medium trial of patients with mild to moderate acne that compared the effectiveness of topical benzoyl peroxide (2.5 percent) and topical

benzoyl peroxide (10 percent) applied twice daily. There were no reported losses to followup.

Trial 22194 was a large multi-center trial of patients (mean age 46 years) with moderate acne, with daily application of topical 5 percent benzoyl peroxide in either an acetone or alcohol base.

This was part of a trial comparing both of these preparations to tretinoin. Subjects, enrollers, and

outcomes assessors were not blinded to treatment assignment. Trial 11895 was a medium split- face design where acne severity could not be categorized. The trial compared the effectiveness of

topical 5 percent benzoyl peroxide in an alcohol base to the same medication in a water base.

Trial 7696 was a medium matched-control trial of patients with moderate acne, with topical 5 percent benzoyl peroxide in a gel and with the same medication in a lotion. Limited information

about methodology was reported. Trial 14997 was a large five-arm trial of benzoyl peroxide 5 percent and 10 percent alone and with tretinoin. 

	Of the many outcomes based on lesion counts, there were no statistically significant

differences among these different treatments, and there was no dose-response effect

demonstrated.

	Side effects were numerically almost identical in the 2.5 percent and 5 percent concentration

groups in Trial 351. In Trial 243, side effects were more prevalent in the 10 percent group,

although P-values were not reported. In Trial 242, side effects were not reported. In Trial 221,

side effects were reported and were similar in the two groups. In Trial 118, side effects were

reported. Burning and erythema occurred with similar frequency between the groups. Scaling and

stinging were reported more frequently with the alcohol-based product. In Trial 76, erythema and

scaling were reported with similar frequency in both groups. In Trial 149, there were statistically

significantly more side effects in the 10 percent group than in the 5 percent group.

D.01.10   –	Benzoyl Peroxide (topical) vs. Benzoyl Peroxide/Urea (topical)

	There was one medium split-face trial, Trial 278,98 of patients with moderate acne. Patient education to minimize improper application and translocation was documented in the report.

There were minimal losses to followup and only minor protocol departures. There was no

statistically significant difference between the preparations for inflammatory and total lesion

counts as well as change in inflammatory lesions. No information about side effects was

reported.

D.01.105  –	Benzoyl Peroxide (topical) vs. Benzoyl Peroxide/Erythromycin (topical)

	See C.03.025.

D.01.11   –	Benzoyl Peroxide (opical) vs. Benzoyl Peroxide/Meclocycline

	See D.06.01.

D.01.12   –	Benzoyl Peroxide (topical) vs. Benzoyl Peroxide/Metronidazole (topical)

	See D.07.02. 

D.01.13   –	Benzoyl Peroxide (topical) vs. Tretinoin (topical)

	See E.05.02.

D.01.14   –	Benzoyl Peroxide (topical) vs. Vitamin A (topical)

	See E.06.02.

D.01.15   –	Benzoyl Peroxide (topical) vs. Oxytetracycline (oral)

	See H.06.02.

D.01.16   –	Benzoyl Peroxide (topical) vs. Isotretinoin (oral)

	See E.02.02.

D.01.17  –	Benzoyl Peroxide (topical) vs. Miconazole/Benzoyl Peroxide (topical) 

	See D.08.01.

D.01.18 –		Benzoyl Peroxide (topical) vs. Chloramphenicol/Hydrocortisone/Sulfur (topical)

	See N.04.05.

D.01.19   –	Benzoyl Peroxide (topical) vs. Isolutrol (topical)

	See N.01.03.

D.02	   –	Chloramphenicol/Sulfur (topical)

D.02.01  –	Chloramphenicol/Sulfur (topical) vs. Chloramphenicol/Hydrocortisone/Sulfur (topical)

	See N.04.03.

D.03    –		Benzoyl Peroxide Combinations

D.03.01  –	Benzoyl Peroxide/Glycolic Acid/Zinc Sulfur (topical) vs. Inert

	There was one medium two-site trial, Trial 310,99 of patients with mild to moderate acne. Data showed that patients and enrollers were blinded to treatment assignment. The performance

of outcomes assessors was monitored by a dermatologist. The trial treatment and placebo

produced statistically significant improvements in lesion counts in the short (4 weeks) and long

(12 weeks) term. However, there was no statistically significant difference between the trial

treatment and placebo at either followup time. 

	Side effects of scaling or tightness of the skin were recorded at 4 and 12 weeks. Although

these effects occurred more frequently in the group treated with the trial medication, the

difference between this and placebo was not statistically significant.

D.03.02   –	Benzoyl Peroxide/Hydroxyquinolone/Hydrocortisone (topical) vs. Benzoyl Peroxide/Hydroxyquinolone (topical) 

	There were two trials: one medium cross-over trial, Trial 16,100 of patients with mild to moderate acne, and one medium four-arm trial, Trial 177,89 of patients whose acne status could not be categorized. Severity in Trial 177 was statistically significantly improved in every arm,

including vehicle. Severity was improved in both arms in Trial 16, without P-values reported. No

between-arms P-values were reported in either trial. Inflammatory and cyst counts in Trial 16

were improved in both arms, but no comparison P-values were reported. No data on side effects

were reported.

D.03.03   –	Benzoyl Peroxide/Chlorhydroxyquinolone/Hydrocortisone (topical) vs. Benzoyl Peroxide/Chlorhydroxyquinolone 

	There was one large (N=196) four-arm trial, Trial 97,90 of patients with mild to moderate acne. Overall change and lesion counts improved in all arms, but only statistically significantly

greater than vehicle arm. It is not clear if the components beyond benzoyl peroxide added

efficacy. There were no side effects data reported.

D.03.04   –	Benzoyl Peroxide/Sulfur (topical) vs. Sulfur (topical)

	There was one large trial (N=113), Trial 82,101 of patients with mild, moderate, and severe acne. Subjects and enrollers were blinded to treatment assignment. At 2 weeks, 46 of 56 subjects

in the benzoyl peroxide/sulfur group were assessed as either “good’ or “excellent” versus 22 of

57 in the sulfur group. This difference was statistically significant at p<0.001. Skin irritation was

reported in five subjects in the benzoyl peroxide/sulfur group and two in the sulfur group.

D.04	   –	Clindamycin/Benzoyl Peroxide (topical)

D.04.01  –	Clindamycin/Benzoyl Peroxide (topical) vs. Inert

	There was one large (N=393) multi-center, multi-arm trial, Trial 21446 of patients with moderate acne. The clindamycin/benzoyl peroxide preparation produced statistically significant

reductions from baseline of inflammatory and non-inflammatory lesions; the vehicle did not.

More subjects had their acne rated as good or excellent in the clindamycin/benzoyl peroxide

group relative to the vehicle group. Side effects reported were erythema, peeling, burning,

dryness, and pruritus. Peeling, particularly, was reported relatively more often in subjects using

the clindamycin/benzoyl peroxide preparation.

D.04.02   –	Clindamycin/Benzoyl Peroxide (topical) vs. Clindamycin (topical)

	See C.01.07.

D.04.03   –	Clindamycin/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	See C.02.03.

D.05	   –	Erythromycin/Benzoyl Peroxide (topical)

D.05.01  –	Erythromycin/Benzoyl Peroxide (topical) vs. Inert

	There was one large four-arm trial, Trial 53102 and one medium trial, Trial 310,99 of patients with mild to moderate acne. Trial 53 had inconsistent ascertainment across arms. In Trial 310, a

pharmaceutical company is listed as a co-author. The performance of assessors was monitored by

a dermatologist. Data showed that subjects and enrollers were blinded, and there were no

reported losses to followup. In Trial 53, erythromycin and benzoyl peroxide, and their

combination, produced statistically significant decreases in inflammatory lesions. The

combination had a numerically larger effect than either constituent, although statistics were not

provided for that comparison. The effect was smaller, and statistically significant only at 10

weeks for non-inflammatory lesions.  In Trial 310, both benzoyl peroxide/erythromycin and

placebo produced significant reductions from baseline in lesion counts at 4 and 12 weeks.

However, neither preparation was superior to the other at either time point. In Trial 310, scaling

or tightness was reported more often in the group treated with benzoyl peroxide/erythromycin.

D.05.015  –	Erythromycin/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical) vs. Erythromycin (topical)

	There was one large, three-arm trial, Trial 53,102 of moderately to severely affected adolescents to young adults. There was inconsistent ascertainment across arms. Improvement in

non-inflammatory and in inflammatory lesions was numerically greater with the combination that

with either constituent, although the statistical significance is given with respect to vehicle. No

other side effects were reported.

D.05.02   –	Erythromycin/Benzoyl Peroxide (topical) vs. Clindamycin (topical)

	There was one large (N=205) multi-center trial, Trial 260,103 of young and older adult women with mild to moderate acne. A pharmaceutical company employee was the primary author. Inter-

site differences in baseline severity were reported to significantly influence the results and were

controlled for in the analysis. Data showed that the subjects, enrollers, and assessors were

blinded to treatment assignment, but assignment was deterministic. 

	Counts of comedones at 4 and 10 weeks and counts of inflammatory lesions at 10 weeks

were statistically significantly lower in the group treated with benzoyl peroxide/erythromycin

than in the group treated with clindamycin phosphate. Overall change scores were similar in both

groups at all timepoints. There were few reported side effects. Three subjects in the benzoyl peroxide/erythromycin group withdrew from the trial compared to none in the clindamycin

phosphate group.

D.05.03   –	Erythromycin/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide/ Glycolic Acid/Zinc Sulfur (topical)

	There was one medium trial, Trial 310,99 of patients with mild to moderate acne. A pharmaceutical company employee was listed as a co-author. The performance of assessors was

monitored by a dermatologist. Data showed that subjects and enrollers were blinded, and there

were no reported losses to followup. Both benzoyl peroxide/erythromycin and placebo produced

significant reductions from baseline in lesion counts at 4 and 12 weeks. Benzoyl

peroxide/erythromycin produced greater reduction in inflammatory lesions at 4 and 12 weeks

than benzoyl peroxide/glycolic acid/zinc sulfur. Scaling or tightness was reported more often in

the group treated with benzoyl peroxide/erythromycin.

D.05.04  –	Erythromycin/Benzoyl Peroxide (topical) vs. Zinc/Erythromycin (topical)

	There was one medium trial, Trial 62,104 of patients whose acne severity could not be categorized. There were no significant differences between the two preparations for physicians’

perceived changes in comedones. Benzoyl peroxide/erythromycin produced greater reductions in

inflammatory lesions and superior clinical assessment scores than did zinc/erythromycin. A

greater number of subjects improved by “50 percent or more” in the benzoyl

peroxide/erythromycin group at all time points. Dryness and irritation was reported by four

subjects in the zinc/erythromycin group and by one subject in the benzoyl peroxide/erythromycin

group.

D.05.05   –	Erythromycin/Benzoyl Peroxide (topical) vs. Group Therapy

	See N.06.03.

D.05.06   –	Erythromycin/Benzoyl Peroxide (topical) vs. Relaxation Training/ Benzoyl Peroxide/Erythromycin: 

	See N.06.03.

D.06	  –		Meclocycline/Benzoyl Peroxide (topical)

D.06.01  –	Meclocycline/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	There was one large (N=102) trial, Trial 30,77 of young adults with moderate acne. There were no losses to followup, but the outcome assessor was not blinded. Comedo count was statistically significantly fewer in the benzoyl peroxide-only group, but not for papules and

pustules. There were two cases of skin discoloration split between both groups.

D.07	  –	Metronidazole/Benzoyl Peroxide (topical)

D.07.01  –	Metronidazole/Benzoyl Peroxide (topical) vs. Inert

	There was one medium trial, Trial 121,105 of patients with moderate to severe acne. A statistically significantly greater number of subjects in the benzoyl peroxide/metronidazole group

were improved by self-assessment and by photographic assessment than in the vehicle group. No

evidence about side effects was reported.

D.07.02   –	Metronidazole/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	There was one medium trial, Trial 121,105 of patients with moderate to severe acne. There were no reported losses to followup. A statistically significantly greater number of subjects in the

benzoyl peroxide/metronidazole group were improved by self-assessment and by photographic

assessment than in the benzoyl peroxide group. No data about side effects were reported.

D.07.03   –	Metronidazole/Benzoyl Peroxide (topical) vs. Oxytetracycline (oral)

	See H.06.03.	

D.08 	  –		Anti-fungal (topical)/Keratolytic 

D.08.01   –	Miconazole/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical) 

	There were three trials, Trial 85,106 Trial 111,107 and Trial 231,108 of patients of mostly late adolescents with moderate to severe acne. While the largest trial (Trial 85) had no losses to

followup, the second largest (Trial 111) did, and both had pharmaceutical industry employees as

co-authors. All three compared the same concentrations of miconazole and benzoyl peroxide, all

applied twice daily.

	Against non-inflammatory lesions, in large-sized Trial 85, not only did both treatments

reduce the count within each arm (although P-values are not provided), but the anti-fungal

combination was more effective than benzoyl peroxide. Both treatments conferred what the

authors in Trial 111 called a “statistically significant” rate at 4 and 12 weeks, although no P-

value was provided. In Trial 231, there was a similar response of comedones; the effect appears

large, but no P-value was provided.

	In the comparison against inflammatory lesions, the results were similar to those seen in non-

inflammatory lesions: within arms, a statistically significant response, but no difference between

arms. There were similar results for total lesions. However, although a medium-sized trial, Trial 111 is one of the few trials that stratified results by gender, and females got a better response in

terms of total lesion from the combination treatment. In Trial 231, the effect of both treatments

was large, but no P-values were reported.

	Patients’ and physicians’ overall assessment in Trial 231 gave the combination statistically

significantly better results than benzoyl peroxide alone. In the same trial, physician’s and

patients’ overall assessment were numerically similar, but no P-values were reported.

	The side effect of irritation was worse in the benzoyl peroxide only arm in Trial 85, about 10

percent versus 1 percent. While the outcome assessment was different in Trial 111, the

conclusion was the same: that benzoyl peroxide alone caused more irritation. The rate was

comparable between males and females in that trial. The side effect rates reported in Trial 231

were about 10 percent for both arms.

D.08.02   –	Miconazole/Benzoyl Peroxide (topical) vs. Isoconazole/Benzoyl Peroxide (topical) 

	There was one small split-face trial, Trial 335,109 of mostly females with mild to moderate acne. The isoconazole arm led to a statistically significant decrease in closed comedones, while

the miconazole did not, but the difference between the two arms was not statistically significantly

different. This pattern was the same for open comedones, papules, and pustules. The miconazole

preparation led to a statistically significant decrease in pustules, and open comedones. The rates

of erythema, scaling, and itching were about 50 percent in both groups. Comparison P-values

were not provided.

Class E.	Retinoid (topical)

E.01    –		Adapalene

	Adapalene is currently available only as 0.01 percent.

E.01.01   –	Adapalene (topical) vs. Adapalene (topical) 

	There were three trials, Trial 78110 and Trial 338,111 comparing 0.1 percent versus 0.03 percent, and Trial 92,112 a split-face trial comparing immediate versus delayed adapalene.   Patients’ acne severity varied from mild to severe; there were moderately severely affected

patients in all trials. Although statistics with respect to baseline are not available, both

concentrations reduced total lesion counts. The higher concentration reduced Leeds severity more

in Trial 78, although this trial had major losses to followup. The higher concentration also

yielded a higher percent change in inflammatory lesion count in Trial 338. In the split-face trial,

Trial 92, erythema and dryness were low and the same. 

E.01.02   –	Adapalene (topical) vs. Tretinoin (topical) 

	There were 11 trials. Seven trials had two-arm design: Trial 49,113 Trial 80,110 and Trial 93114 (split-face), Trial 63,115 Trial 100,116 Trial 140,117 and Trial 306.118  These all involved the same concentration of tretinoin, 0.025 percent. There were four multi-arm trials: Trial 78,110 comparing doses 0.1 percent, 0.03 percent, and tretinoin 0.025 percent with adapalene; Trial 119,119 a seven- arm trial with a range of concentrations from 0.025 percent to 0.1 percent in different vehicles;

Trial 338,111 a three-arm trial of 0.03 percent to 0.025 percent; and Trial 120,119 a six-arm, split- face trial, with tretinoin concentration of 0.025 percent to 0.1 percent and vehicles (gel and

cream). The total is over 1,700 patients, with about one-third in Trial 63. The patients studied

varied in severity from mild to severe; all trials had moderately affected subjects. Most of the

trials were demonstrably randomized.

	Across outcomes, the two treatments were mostly comparable in efficacy. The effect was

about 50 percent reduction in total lesions, requiring between 4 weeks (Trial 78) and 12 weeks

(Trial 338) to achieve this effect. Adapalene had greater intra-patient percent change in non-

inflammatory lesions in one trial (Trial 306) and in inflammatory lesions in two (Trial 306 and

Trial 338).

	Adapalene fared better in terms of side effects. Tretinoin had more patients with

desquamation (a score of 1 versus adapalene’s 0) and slightly more total adverse skin symptoms (Trial 93), more scaling (Trial 306, Trial 80) or dryness (Trial 80) or “tightness” (Trial 49), more

burning (Trial 80, Trial 49) at 2 and at 12 weeks, more “adverse reactions” (Trial 63), and more

patients discontinuing therapy because of adverse effects. In one trial, adapalene caused more

burning or itching (Trial 100). In a split-face trial (Trial 93), patients were more often intolerant

of tretinoin; and of patients asked their preferences after trial completion, more favored

adapalene or the method of application (P = 0.001), although patients were not blinded and the

trial was funded by adapalene’s producers. 

E.02 	  –		Isotretinoin (topical)

E.02.01  –	Isotretinoin (topical) vs. Inert (topical) 

	There were three trials, Trial 54,120 Trial 173,87 and Trial 202121 (the last two being three-arm trials), of patients with mostly mild to moderate severity. Topical isotretinoin proved to be

statistically significantly more effective (although the authors make the claim without providing

the actual significance levels) in terms of Cook or Leeds severity change, inflammatory lesions,

and non-inflammatory lesions, starting at 4 weeks and extending to 14 weeks. In Trial 202, there

was no statistical difference with respect to papules or to comedones. The effect was on the order

of 40 percent change in severity or lesion count. In terms of adverse effects, there was no

statistically significant difference between the therapies. 

E.02.02   –	Isotretinoin (topical) vs. Benzoyl Peroxide (topical) 

	There was one comparison, Trial 173,87 two arms of a three-arm trial. In this trial of 77 mild and moderately affected patients, benzoyl peroxide conferred mildly better improvement (P =

0.01). For both treatments, Leeds severity dropped to a mean of 1 after 4 weeks, and 0 after 12

weeks. Both inflammatory and non-inflammatory lesions were improved. The improvement in

counts was on the order of 20 percent for both. Local reactions (roughness) were few and similar. 

E.02.03   –	Isotretinoin 0.1 percent (topical) vs. Isotretinoin 0.05 percent (topical) 

	There was one medium trial, Trial 202.121 Each concentration had a statistically significant effect on papule and comedo counts, and that effect was statistically equivalent between the

arms. Side effects were limited to one patient dropping out due to erythema in the 0.05 percent

group. 

E.02.04   –	 Isotretinoin (topical) vs. Tretinoin (topical) 

	There were two small trials, Trial 90122 and Trial 98,123 of patients with moderate acne in Trial 90, but not categorizable in Trial 98. Trial 90 had no losses to followup, but patients and

providers were not blinded adequately, while Trial 98 had arms that were not completely

comparable. Decrease in counts of comedones and inflammatory lesions at 4 and 12 weeks were

large and comparable. Only Trial 90 provides data on adverse reactions. The rate of side effects

(irritation) was about 50 percent in isotretinoin patients, and about 65 percent (stinging,

erythema, and desquamation) in the tretinoin patients. Comparison P-values were not provided.

E.03 	   –	Motretinide 

E.03.01   –	Motretinide (topical) vs. Vehicle (topical) 

	There are two trials: Trial 61,124 a small trial with major losses to followup, noncomparability of the arms, and the execution differing, thereby, from the design; and a large trial, Trial 60,125 by the same authors, of mild through moderate acne in a three-arm trial. Although motretinide led to

statistically significant changes with respect to baseline in Trial 61, the sample size was so small

that the decrease was not statistically significantly different from the vehicle effect. In the larger

trial, the subjective rating of total lesions change was not statistically significantly different from

vehicle. There was a high incidence, but no statistically significant differences, in side effects

(erythema, desquamation, pruritus, burning).

E.03.02   –	Motretinide (topical) vs. Motretinide (topical) 

	There was one medium trial, Trial 253,126 of patients with moderate through severe acne. Motretinide twice daily was compared against itself as a once daily administration. Both led to statistically significant and meaningful decreases in papules and pustules, and in overall change,

but neither was better than the other. Side effects were not reported. 

E.03.03   –	Motretinide (topical) vs. Tretinoin (topical) 

	There were three trials, Trial 59,127 Trial 253,126 and Trial 60,125 of patients with the full range of acne severity. Trial 60, being the largest, had mild through moderate degrees of severity. Trial

59 had arms comparable on a number of characteristics beyond age and severity, but the trial was

weakened by major losses to followup.

	The improvement in total lesion count in each arm was statistically significant in Trial 59, but

not statistically significantly different between arms. Papule and pustule counts were similarly

effectively reduced in Trial 253, with no statistically significant difference between arms. In Trial

60, over half the patients in the two arms had a 50 percent or more improvement, and, again,

there was no statistically significant difference between the two arms. 

	Side effects (pruritus, burning, erythema, and desquamation) occurred in most patients in the

tretinoin group in Trial 60, and statistically significantly less so, but still very often, in the

motretinide group. The absolute rate was lower in Trial 59, but tretinoin’s rate was still

statistically significantly greater than motretinide’s. 

E.04	  –		Retinyl Beta-glucuronide 

E.04.01   –	Retinyl Beta-glucuronide (topical) vs. Vehicle (topical) 

	There was one small trial, Trial 145,128 a split-face trial of males with mild to moderate acne using stratified randomization and no losses to followup. The retinoid conferred a statistically

significant decrease in non-inflammatory lesions at 18 weeks. Most other outcomes were

equivalent numerically and statistically. Adverse reactions were equivalent. 

E.04.02   –	Retinyl Beta-glucuronide (topical) vs. Tretinoin (topical) 

	There was one small trial, Trial 146,128 including patients with mild to moderate acne. Both treatments led to a statistically significant decrease in physicians’ rating of overall change. No

outcome differed in a statistically significant way between the treatments. Almost all tretinoin-

treated patients had erythema, drying, peeling or cracking, while the retinyl group did not. 

E.05.    –	Tretinoin

E.05.01   –	Tretinoin (topical) vs. Inert (topical) 

	The strengths of tretinoin examined ranged from 0.025 percent to 0.1 percent, and included

both gel and cream. There were six trials: five three-arm trials, Trial 58,129 Trial 60,125 Trial 198,130 Trial 220,131 and Trial 219,132 and one two-arm trial, Trial 270,133 comprising 10 relevant comparisons. Trial 58, Trial 60, and Trial 198 all involved a comparison with 0.05 percent; the

remaining comparison concerned the weaker 0.025 percent strength. Trial 58, Trial 220, and

Trial 219 were multi-center trials. Most patients had mild to moderate acne, except for patients in

Trial 58, where the acne was severe, and in Trial 198, where we could not categorize the severity. 

	Four trials assessed global, overall change. In three (Trial 60, Trial 198, and Trial 270), the

change was large and statistically significant. In Trial 219, the change was large, but not

statistically significant. Most trials measured lesion counts. Total lesion counts were statistically

significantly improved only in one trial (Trial 219), where there was borderline statistical

significance at 12 weeks. The magnitude was fairly large (about 40 percent), however.  Tretinoin

led to a greater decrease in non-inflammatory lesions in all trials, although statistically significantly in only three of the four trials. Inflammatory lesions decreased as well, but fewer

trials achieved a statistically significant result compared with vehicle. Only Trial 59 and Trial

270 distinguished papules from pustules, and papules were statistically significantly improved

only with the higher tretinoin dose in the first trial, but both pustules and papules were improved

in the second.

	Side effects were frequent. In two trials (Trial 58 and Trial 60), erythema and other local

symptoms were almost universal early on, but then dropped off. Local symptoms included

erythema, peeling, pruritus, burning, and irritation. The frequency was almost always statistically

significantly greater than in the inert control. The frequency was not insignificant, however, in

the control groups. One trial (Trial 220) reported on systemic symptoms, which occurred about

one-third of the time, but not statistically significantly more often in the tretinoin group.

E.05.015  –	Tretinoin (topical) vs. Salicylic Acid/Resorcinol/Sulfur (topical)

	There was one medium trial, Trial 84,134 of tretinoin at 0.05 percent and 0.02 percent strengths, and the keratolytic. Numerous methodological qualifications included lack of blinding,

major losses to followup, noncomparable arms, and inconsistent ascertainment across arms. The

single outcome of qualitative improvement appeared greater for the higher tretinoin

concentration, but P-value was not provided. Side effects were comparable.

E.05.02   –	Tretinoin (topical) vs. Benzoyl Peroxide (topical) 

	There were three trials. Trial 149 97 was a large five-arm trial of benzoyl peroxide 5 percent and 10 percent alone and with tretinoin in Indonesian patients where acne severity cannot be

categorized. There was one medium trial, Trial 38,135 and one large trial, Trial 221,94 of patients with moderate acne. The first trial used lower strength (0.025 percent) and the second, higher

(0.1 percent).

	In Trial 38, there was early increase in papules in tretinoin (data abstracted but not shown in

the evidence table), but statistically significant improvement in comedones, papules, and pustules

by 12 weeks. The decrease was statistically significantly greater in the tretinoin group for

comedones and papules, but the differences were small. Both patients and clinicians rated the

tretinoin group as more improved. In Trial 221, there was over a 30 percent decrease (after 8

weeks) in the tretinoin group for papules, pustules, and, most strongly, for comedones. The

benzoyl peroxide groups had a greater effect on papules, but otherwise had a statistically

significant equivalent effect. Qualitative assessment of severity change was the same in both

groups. In Trial 149, the amount of time to 75 percent or more improvement was not statistically

significantly greater in the benzoyl peroxide group. Overall change was highest in the

tretinoin/benzoyl peroxide 5 percent group, and statistically significantly greater than the other

groups.

	Side effects (erythema, irritation, soreness) were few in Trial 38 and the same in the two

arms. In Trial 221, the rate of these side effects was about 20 percent and not statistically

significantly different for the two arms. 

E.05.03   –	Tretinoin (topical) vs. Adapalene (topical)

	See E.01.02.

E.05.04   –	Tretinoin (topical) vs. Azelaic acid (topical) 

	There were two large trials, Trial 18832and Trial 316.136  Acne severity was mild in the second trial and could not be categorized in the first. Trial 188 used a higher strength of tretinoin, and

treatment continued for 6 months.

	Change in non-inflammatory lesions was comparable in the tretinoin arms of the two trials,

although neither within- or between-arm P-values are supplied. Change in papules was greater

and statistically significantly so in the azelaic group in Trial 316.

	In Trial 188 (higher strength, longer duration of treatment), side effects of erythema and

scaling occurred in about 30 percent of subjects, and were statistically significantly greater than

in the azelaic (about 20 percent) group. In Trial 316, the same side effects occurred and

statistically significantly more frequently in the tretinoin than in the azelaic group.

E.05.05   –	Tretinoin (topical) vs. Isotretinoin (topical)

	See E.02.04..

E.05.06   –	Tretinoin (topical) vs. Retinyl Beta-glucuronide (topical)

	See E.04.02..

E.05.07   –	Tretinoin (topical) vs. Tretinoin (topical) 

	There were eight trials. Three trials were large three-arm trials: Trial 58,129  Trial 220,131 and Trial 219.132  There were two medium three-arm trials, Trial 84134 and Trial 198.130  There were three small multi-arm trials: Trial 119119 (seven arms), Trial 120119 (six arms), and Trial 302137  (four arms). Trial 119, Trial 120, and Trial 302 were very small (less than 10 patients per arm) and very short (3-week) multi-arm trials. Trial 58 and Trial 220 were multi-center trials.  One-

quarter of the patients had severe acne (Trial 58); one-third had mild acne (Trial 220); one-

quarter had mild to moderate acne (Trial 219); and for the remainder, severity could not be

categorized. In fact, not all subjects in Trial 119 and Trial 120 had acne, since these were trials to

evaluate tolerability and not effectiveness. Pharmaceutical employees were co-authors in these

two trials. Trial 302 suffered from major protocol departures, although losses to followup were

minor. Trial 84 reported comparable improvement, but no P-values, between the two strengths of

tretinoin. The strengths of tretinoin examined ranged from 0.025 percent gel through 0.1 percent

cream.

	Two trials evaluated overall change. In Trial 198, both lower and higher dose tretinoin

conferred improvement or marked improvement that was not statistically significant between the

two groups. In Trial 219, the addition of polyolprepolymer-2 did not increase overall improvement. The three trials that reported total lesion count change (Trial 58, Trial 198, and

Trial 220) showed no statistically significantly different change across tretinoin strengths. Four

trials reported on non-inflammatory lesions specifically (Trial 58, Trial 198, Trial 220, and Trial

302).  One trial (Trial 58) yielded a statistically greater decrease from the 0.05 percent

preparation compared with the 0.025 percent, but the absolute difference was small. The same

trials reported on inflammatory lesions. Only two trials demonstrated statistically significant

differences in efficacy, and the magnitude of these differences was small.

	All trials reported on side effects. There was a strength-response relationship demonstrated in

Trial 58, in Trial 119, and in Trial 120. Side effects from 0.1 percent strength were so frequent

and severe that most subjects stopped using the treatment. Side effects noted included erythema,

peeling, and irritation. The addition of polyolprepolymer-2 in Trial 219 did not improve the side

effect rate.

E.05.075   –	Tretinoin (topical) vs. Tretinoin/Clindamycin (topical)

	See G.02.02.

E.05.078  –	Tretinoin (topical) vs. Motretinide (topical)

	See E.03.03.

E.05.08    –	Tretinoin (topical) vs. Neomycin/Methylprednisolone (topical) 

	There was one medium multi-center, split-face trial, Trial 13,138 of patients with the full range of acne severity. Although 18 centers were involved, the authors reported no details regarding

baseline characteristics, beyond gender and age; so it is difficult to assess the generalizability of

their findings. The outcomes are hard to interpret in the absence of baseline data, but the actual

change scores and comedo counts appear the same in the two groups. No comparison statistics

were provided. Qualitative assessment (number of patients comedo-free, inter-treatment patient

preference) was the same in both groups. Side effect rates of burning, stinging, dry skin, and

erythema are equal in the two groups.

E.05.09    –	Tretinoin (topical) vs. Chloramphenicol/Hydrocortisone (topical) 

	There was one medium multi-center trial, Trial 37,139 of patients with moderate acne. Evidence of randomization is good, but there were major losses to followup, and the paper was

co-authored by a pharmaceutical employee. Patients rated statistically significantly “marked

improvement” after 12 weeks in both groups, with no statistical difference between the groups.

Both groups had decreases in all lesion types (including cysts), but the baseline numbers were

small. Qualitative assessment of improvement was the same in both group. The authors provided

no data on side effects.

E.06	  –		Vitamin A

E.06.01  –	Vitamin A (topical) vs. Inert (topical) 

	There were two medium trials, Trial 35140 and Trial 34,141 of patients with mild to moderate acne. Trial 34 had no losses to followup. Trial 35 used a matched-control design.

	In Trial 35, there was a marked difference numerically between the groups for comedones

and papules, although P-values were not provided and cannot be calculated. Subjective

assessment of overall change was statistically significant. There does not appear to be a

difference with respect to pustules, but the absolute number of pustules is small, meaning a larger

sample size would be needed to discern a difference. This is one of the few trials to stratify

findings by sex. The effect of vitamin A appears to have been different for males and females:

papules were reduced in males, but not in females, while comedo counts were reduced a similar

proportion (60-80 percent). Assessments of overall change were statistically significant in both

strata. In Trial 34, assessed response was better in the treated group; our calculated P-value

demonstrated statistical significance.

	 In Trial 34, every patient treated with vitamin A had erythema, while the control group had

none. Trial 35 provided no side effect data.

E.06.02   –	Vitamin A (topical) vs. Keratolytic (topical) 

	There was one large three-arm trial, Trial 27292 (N=189), with benzoyl peroxide and with sulfur/resorcinol as comparators. Percent change at 14 weeks was numerically markedly better in

the vitamin A arm than in either comparator arm, although P-values were not provided nor could

be calculated. No side effect data were provided. 

E.06.03   –	Vitamin A (topical) vs. Oxytetracycline (oral) 

	There was one large multi-center trial, Trial 57142 at 2 university clinics and 13 private clinics, for a total of 238 patients 11 to 44 years old, where acne severity cannot be categorized. The

enroller/treater was adequately blinded, and the arms were comparable by age, sex, skin color,

skin type, and number and type of acne, but there were major losses to followup. The trial

compared topical vitamin A, oral oxytetracycline, and the two together. 

	Across the three groups, improvement in inflammatory and non-inflammatory lesions was

high (over half of patients achieving over 50 percent improvement), but no differences were

statistically significant. The rate of side effects was high: up to 25 percent with erythema and

desquamation in the vitamin A group and about 8 percent in the antibiotic group, but the

between-arm P-value addresses all side effects together and is not statistically significant. 

Class F.	Retinoid (topical)/Keratolytic

	No comparisons are available.

Class G.	Retinoid (topical)/Anti-bacterial (topical)

G.01    –	Tretinoin/Erythromycin (topical)

G.01.01   –	Tretinoin/Erythromycin (topical) vs. Erythromycin (topical) vs. Tretinoin (topical) vs. Vehicle

	There was one small four-arm trial, Trial 238143 of patients with moderate to severe acne. Physicians’ assessment of overall change appeared greater in the combination group, less so in

each component group, and least in the vehicle group. No comparison P-values were reported.

No side effect data were reported.

G.02	  –		Tretinoin/Clindamycin (topical)

G.02.01   –	Tretinoin/Clindamycin (topical) vs. Clindamycin (topical)

	There were two small trials, two-arm Trial 46144 and three-arm Trial 283,145 and two large two-arm trials, Trial 45144 and Trial 47,144 all of adolescents and young adults with moderate to severe acne (some patients with mild acne in Trial 283). In Trials 45, 46, and 47 (performed by

the same investigators), there were no losses to followup, but inconsistency in outcome

ascertainment and noncomparable arms. In Trial 283, recruitment and treatment assignment were

stratified by gender.

	The combination treatment resulted in statistically significant, but small, improvements in

non-inflammatory, but not inflammatory, acne in Trials 45 and 47.  The overall severity score

was also statistically significant, but small, in these two trials.  Only Trial 283 reported on side

effects, which were numerically fewer in the clindamycin group but statistically different across

the three arms of that trial.

G.02.02   –	Tretinoin/Clindamycin (topical) vs. Tretinoin (topical)

	There were two large trials, Trial 43144 and Trial 44,144 and one medium trial, Trial 42,144all two-arm trials of moderately to severely affected adolescents to young adults. All had no losses

to followup but had noncomparable arms and inconsistent ascertainment across arms.

	Of severity, inflammatory, and non-inflammatory changes, inflammatory change with respect

to baseline was greater in the combination group in Trials 42 and 43, but not statistically greater

in Trial 44. Severity change was statistically significantly greater in the combination group only

in Trial 43, at 12 weeks. Side effects were not reported.

G.02.03   –	Tretinoin/Clindamycin (topical) vs. Tetracycline (topical)

	There was one small three-arm trial, Trial 283,145 of adolescents and young adults, stratified by gender recruitment and treatment assignment. There were no statistically significant

differences in effectiveness or in side effects.

G.03.01   –	Tretinoin/Benzoyl Peroxide (topical) vs. Benzoyl Peroxide (topical)

	See D.01.09.

Class H.	Anti-bacterial (oral)

H.01.    –	Clindamycin

H.01.01   –	Clindamycin (oral) vs. Inert (oral) 

	There was one medium trial, Trial 56,146 of adolescents with moderate acne. Changes in non- inflammatory and inflammatory lesions were large (48 percent and 75 percent decrease,

respectively) and statistically significant at 6 and 13 weeks. Adverse reactions, gastrointestinal in

particular, were the same; there was numerically more mild diarrhea in the clindamycin group. P-

values were not provided.

H.01.02   –	Clindamycin (oral) vs. Tetracycline (oral) 

	There were two small trials, Trial 265147 and Trial 275,148 of moderately affected patients (adolescents exclusively in Trial 265). Trial 265 was afflicted with major losses to followup,

while Trial 275 made explicit its education of patients for applying the medication.

	In Trial 265, efficacy was numerically equivalent for overall change, for severity, and for

lesion count, at 4 and at 8 weeks, but no P-values were provided or could be calculated. In both

treatments, the effect was about a 50 percent decrease in lesion counts, using group means. In

Trial 275, overall change, according to patients, were equivalent for the two groups, about two-

third of patients having been “much improved.”

	In Trial 265, esophagitis or mild diarrhea/cramping was present in equal, small numbers in

both groups. In Trial 275, two patients withdrew from the clindamycin group, none from the

tetracycline group.

H.02	  –		Demethylchlortetracycline

H.02.01   –	Demethylchlortetracycline (oral) vs. Placebo (oral) 

	There was one small trial, Trial 162,149 one medium trial, Trial 192,150 and three large trials, Trial 312,151 Trial 193150 and Trial 71,152 the last two being cross-over trials.  Acne severity was moderate to severe in one trial (Trial 162), mild through severe in another (Trial 312), and not

categorizable in the others. Only one trial (Trial 71) provided the gender breakdown. Although it

had a cross-over design, Trial 71 had enough errors in assignment that it had, effectively, non-

random assignment. Trial 162, a parallel-design trial, had too many placebo patients receive the

anti-bacterial (unplanned cross-over). In two trials, the dose was 150 mg once daily; in the other

two, 150 mg four times daily. 

	Assessment of relative improvement was statistically significantly greater for

demethylchlortetracycline only in Trial 162. The difference was not statistically significant in the

other four trials.

	In Trial 162 (higher dose), about one-third of patients reported photosensitivity; other patients

report gastrointestinal (GI) disturbance and photo-onycholysis, none of which occurred in

placebo-treated patients (P=0.01). In Trial 71 (higher dose), 10 percent of patients complained of

photosensitivity (versus less than 1 percent in the placebo group).

H.02.02   –	Demethylchlortetracycline (oral) vs. Phenethicillin (oral)

	There was one medium trial, Trial 312,151 of patients with mild through severe acne. Physicians’ assessment of overall change was numerically and statistically the same. Similarly,

patients’ assessment and photo-based severity assessment were both the same in the two

treatment groups.

H.02.03   –	Demethylchlortetracycline (oral) vs. Tetracycline (oral) 

	There were two large trials, Trial 70153 and Trial 71,152 of patients with non-categorizable acne severity. Trial 70 had biased ascertainment because more severely affected patients finished

their course of antibiotics earlier. Treatment assignment in Trial 71 was made incorrectly in

about one-quarter of the patients.

	In Trial 70 (lower dose), physicians’ assessment of overall change was better in the

tetracycline group (P=0.01), although there were eight (about 10 percent) relapses 15 weeks after

therapy in the tetracycline group. In Trial 71 (higher dose), severity change was not statistically

significantly different. The actual improvement rate was higher in Trial 70 than in Trial 71.

	In Trial 71 (higher dose), 10 percent of demethylchlortetracycline assigned patients

complained of photosensitivity. In Trial 70, there were numerically more side effects (all GI-

based) in the tetracycline group, but no statistics are provided.

H.03	   –	Doxycycline 

H.03.01   –	Doxycycline (oral) vs. Placebo

	There was one large cross-over trial, Trial 273,154 of patients with mild acne. The trial was limited by major losses to followup. Decreases in inflammatory counts was statistically

significant in the doxycycline arm in both phases. Assessment of improvement, however, was not

different for comedones or for cysts. There were zero side effects in either group.

H.03.02   –	Doxycycline (oral) vs. Fusidic (oral)

	There was one large trial, Trial 1155 (N=110), of late adolescents with mild-moderate acne. Patients were not blinded, and a co-author was a pharmaceutical employee. Total lesion count, at

6 and 10 weeks, dropped significantly in both groups so that the effectiveness was statistically significant within each arm, but not statistically significant across arms. Assessments of overall

change, by patient and by investigator, were also not statistically different. There were

numerically more side effects in the fusidic acid group (4 vs.1), but no P-values were reported.

H.03.03   –	Doxycycline (oral) vs. Erythromycin Stearate (oral)

	There was one medium two-site trial, Trial 25,156 of young adults with moderate acne. The trial had excellent methodological control. Severity decreased to mild in both groups; P-value

was not provided. Change in inflammatory lesions was large and statistically significant within

each group, but not statistically different across groups.

H.03.04   –	Doxycycline (oral) vs. Minocycline (oral) 

	There was one medium trial, Trial 257,157 and two small trials, Trial 311158 and Trial 155,159  of patients with a full range of acne severity. In Trial 257, a co-author was a pharmaceutical

employee. In Trial 155 there were major losses to followup.

	In Trial 311, there was no difference in severity at 12 weeks. In Trial 257 and Trial 155, there

were many lesion-based outcomes. In Trial 155, investigators attempted to obtain patients’

preferences on a 100 cm visual analogue scale, but the responses were too inconsistent to be

usable. Although no differences were statistically significant, both treatments were effective,

decreasing counts by about 50 percent by 12 weeks for both inflammatory and non-inflammatory

lesions; P-values were not supplied by the authors. 

	Side effects (dyspepsia, headache, nausea, vertigo) were few and comparable in the two

groups.

H.04	   –	Erythromycin

H.04.01   –	Erythromycin (oral) vs. Doxycycline (oral)

	See H.03.03.

H.04.02   –	Erythromycin Base (oral) vs. Erythromycin Stearate(oral) 

	There were two trials: one small trial, Trial 24,160 of patients with moderate acne over only 2 weeks, and one small seven-arm trial, Trial 340,161 of patients with moderate to severe acne treated between 6 and 18 months. In Trial 340, preference over placebo was evaluated, but

difficult to interpret. In Trial 24, only papule counts were reported. The counts were significantly

(and statistically) decreased with respect to baseline in each arm, although the stearate did

statistically significantly better. Side effects (gastrointestinal distress) appeared in both groups,

but the difference was not statistically significant.

H.04.03 –	Erythromycin (oral) vs. Tetracycline (oral)

	There were four trials: two small trials (Trial 6162  and Trial 36140), one small seven-arm trial (Trial 340161), and one large multi-center trial (Trial 125163).  Severity ranged from mild to moderate (Trial 125) to moderate (Trial 36), to severe (Trial 340); baseline acne severity could

not be categorized in Trial 6. Trial 36 included student health centers, in addition to

dermatologists’ offices and academic clinics, but had a pharmaceutical co-author. Doses varied:

Trial 6 compared erythromycin 250 mg twice daily with tetracycline, 250 mg twice daily; Trial

36, erythromycin acistrate 200 mg once daily versus tetracycline 250 mg once daily; and Trial 125, erythromycin 500 mg once daily versus tetracycline of unknown dose.

	Trial 36 reported that, on the face, back, and chest, severity improved at 12 and 24 weeks,

with a within-group P-value of 0.05, but between groups, the between-arm P-value was not

statistically significant. Trial 125 provided no P-values, but numerically, the effects were the

same for both treatments for comedones, papules, and pustules. Patients’ subjective assessments

of change were numerically similar for the two treatments as well. Trial 6 also did not present P-

values but presented numerically similar assessments of severity change in the two treatments.

Trial 340 presented inter-treatment comparison. Although difficult to interpret (they are based on

comparison to placebo), a few more patients preferred two different types of tetracycline

(phosphate, citric acid, but not novobiocin) than preferred erythromycin.

	Trial 6 had about 8 percent of patients with side effects, equal in the two groups. Trial 36 had

up to 20 percent side effects, again equal in the two groups numerically. In Trial 125, there were

again about 8 percent side effects. Numerically, more patients dropped out of erythromycin due

to side effects, but these are probably statistically not significant.

H.04.04   –	Erythromycin (oral) vs. Triacetyl-oleandomycin (oral) 

	There was one small seven-arm trial, Trial 340,161 of patients with moderate to severe acne treated between 6 and 18 months. Preference over placebo was evaluated, but difficult to

interpret. More patients preferred triacetyl-oleandomycin over placebo than preferred

erythromycin over placebo. No side effect data were reported.

H.04.05   –	Roxithromycin 150 mg (oral) vs. Roxithromycin 300 mg (oral) 

	There was one small trial, Trial 4,164 where acne severity cannot be categorized. A single outcome, severity change, was high for both groups, and not statistically significantly different.

No side effect data were reported.

H.04.06   –	Oleandomycin (oral) vs. Ttriacetyl-oleandomycin (oral) 

	There is one large trial, Trial 247165 (N=142), of patients where acne severity cannot be categorized. The authors reported only one outcome, physicians’ perception of overall change,

which was “excellent” in about one-quarter of cases in each arm, and not statistically

significantly different. No data on side effects were reported.

H.05	  –		Minocycline 

H.05.01   –	Minocycline (oral) vs. Placebo (oral)

	There was one medium cross-over trial, Trial 161,166 and one large cross-over trial, Trial 273.154  Acne severity was mild in Trial 273, and could not be categorized in Trial 161. The high- dose trial (Trial 273) was weakened by major losses to followup.

	Acne severity in Trial 161 improved within the minocycline arm to a statistically significant

extent and it improved, but not to a statistically significant extent in the placebo arm, in both

phases of the cross over. However, a between-arm P-value was not provided. Inflammatory

lesion counts in Trial 273 are improved by minocycline to a statistically significant extent in both

phases. Non-inflammatory lesions, nodules, and cysts were improved, but not apparently more

than by placebo; between-arm P-values were not provided.

	There were two side effects (vertigo and urticaria) leading to patient withdrawals in Trial

161, and zero side effects reported in Trial 273. 

H.05.02   –	Minocycline (oral) vs. Clindamycin (topical)

	There were two medium trials, Trial 268167 and Trial 307,168 of patients with moderate to severe acne. Trial 268 was a multi-center trial of student health centers that used balanced, block

randomization. Trial 307 was a matched-control trial.

	Overall assessment at 4 and 12 weeks was equivalent between the two groups in Trial 268,

and was highly statistically significant within each group. Severity was not statistically

significantly different between arms in Trial 307. Lesion-count decreases were equivalent

between the two groups in both trials. Only Trial 268 documented statistically significant

decreases within each group.

	Side effects (six patients with allergy, diarrhea, impetiginization, dryness, and stinging) were

few and similar between the groups.

H.05.03   –	Minocycline (oral) vs. Doxycycline (oral)

	See H.03.04.

H.05.04   –	Minocycline (oral) vs. Tetracycline (oral)

	There were two large two-arm trials, Trial 72169 and Trial 171,170  and one medium trial, Trial 298,171 of patients with moderate to severe acne. Trials 72 and 298 evidenced good blinding, and in Trial 298, agreement in assessment among patients, reviewers, and investigator was measured

and was high (between 60 and 86 percent). Trial 171 had major losses to followup and

inconsistent ascertainment across arms.

	Severity change was not statistically significantly different between the two arms in Trial 298

or Trial 171. Lesion counts were improved by both treatments in Trial 72, having reduced

comedones, papules, and pustules about 30 percent by 19 weeks; P-values were not provided. 

	Side effects (nine total in Trial 298) were not statistically significantly different between the

arms, including GI and vaginal symptoms. There was one case of hives in the minocycline group

in Trial 171.

H.06    –		Oxytetracycline 

H.06.01   –	Oxytetracycline (oral) vs. Placebo (oral)

	There was one large cross-over trial, Trial 250172 (N=76), in patients with moderate to severe acne. There were major losses to followup and there were irregularities in execution. Severity

change favored oxytetracycline in both phases of the cross-over (by our calculated chi-square

test). Over half the patients had an “excellent” response in the oxytetracycline arm. No side effect

data were reported.

H.06.02   –	Oxytetracycline (oral) vs. Benzoyl Peroxide (topical)

	There was one small three-arm trial, Trial 255,84 of patients with moderate acne. Data were provided on many outcomes on the face, chest, and back. For oxytetracycline, many of these

results were statistically significant within its arm. Although the benzoyl peroxide arm had no P-

values listed, the numerical values were similar to those in the anti-bacterial group. The

differences between the two arms were not statistically significant. There were six side effects

reported (GI symptoms, severe facial reaction, vaginal candidiasis).

H.06.03   –	Oxytetracycline (oral) vs. Benzoyl Peroxide/Metronidazole (topical)

	There was one medium trial, Trial 123,105 of young adults with moderate to severe acne. Assessments of overall change by both patient and physician were about the same in the two

groups (about one-third “much improved”) and not statistically significantly different. No side

effect data were reported.

H.06.04   –	Oxytetracycline (oral) vs. Vitamin A (topical) 

	See E.06.03.

H.06.05   –	Oxytetracycline (oral) vs. Tetracycline (oral)

	There was one small three-arm trial, Trial 255,84 of patients with moderate acne. Both treatments reduced face severity and comedonal count with statistical significance.  Both also

reduced the inflammatory lesion count, although only tetracycline’s effect reached statistical

significance, but the difference between the two groups was not statistically significant. There

were four side effects (GI symptoms).

H.06.06   –	Oxytetracycline (oral) vs. Cotrimoxazole (oral)

	There was one small matched-control trial, Trial 152,173 of only 16 patients with mild through severe acne. There was no statistically significantly different preference for one treatment over

the other. There was one report of side effects (flatulence/abdominal pain).

H.06.07   –	Oxytetracycline (oral) vs. Trimethoprim (oral)

	There was one small trial, Trial 128.174 Overall change was mostly “fair,” but not statistically significantly different between arms. Lesion counts were statistically significantly reduced in

both arms, with no statistically significant difference between the arms. Side effects (five

patients) reported were not statistically significantly different between arms.

H.07	  –		Sulfa Antibiotics

H.07.01  –	Cotrimoxazole (oral) vs. Vehicle (oral)

	There were two medium cross-over trials, Trial 160175 and Trial 223.176  Neither trial specified the patients’ acne severity, and Trial 223 did not provide a sex and age breakdown, but did

provide evidence of good blinding. In Trial 160, improvement in severity was large and

statistically significant, whether treated first or second with the antibiotic. There was no

improvement from the vehicle. No between-arm P-value was provided. In Trial 223, the way that

the lesion data were reported precludes our making a comparison. However, that trial provided

some side effect data (dizziness, headaches, red macular rash), which were too few to make

inferences.

H.07.02   –	Sulfadimethoxine (oral) vs. Placebo (oral)

	There was one large cross-over trial, Trial 44,177 of patients with severe acne. There were no losses to followup. The only outcome is physicians’ preference across the two treatment phases,

comparing treatments within patients. The P-value we calculated for the authors (based on chi-

square) is 0.001. There were no data on side effects.

H.08    –		Tetracycline

H.08.01   –	Tetracycline (oral) vs. Inert (oral)

	There were nine trials of tetracycline 250 mg at different dosing schedules. Trials of twice

daily administration were: Trial 69,178 Trial 201,179 Trial 10,80 Trial 33,44 Trial 23,81 Trial 313,83 and Trial 136, 180 the last five being three-arm trials. Trials of four-times-daily administration were Trial 71152 and Trial 349,181 a four-arm trial. Six trials gave baseline severity information: Trial 33 studied mildly affected patients; Trial 10, Trial 23, Trial 249, and Trial 136 studied moderately affected subjects; Trial 313 patients had mild to moderate acne. Of the trials that

provided ages, all were late adolescent/young adult. Trial 71 and Trial 313 were generalizable to

college or local populations of young adults. Trial 23 and Trial 349 were properly randomized

and Trial 201 had proper blinding. Trial 71 was a cross-over trial; but because of errors in

randomization, almost all subjects received tetracycline first. Trial 23 had a pharmaceutical

employee as a co-author.

	For outcomes of relative improvement, and in all nine trials, tetracycline conferred

statistically significantly greater improvement than placebo as early as 6 weeks and as late as 13.

The magnitude of the improvement cannot be summarized from the data reported. Trial 33

provides some lesion count data: by 8 weeks, the decrease in inflammatory lesions was

statistically significantly different from placebo.

	Five trials (Trial 33, Trial 69, Trial 201, Trial 349, and Trial 136) reported on side effects; the

total number of affected patients was 15.

H.08.02   –	Tetracycline (oral) vs. Clindamycin (topical)

	There were five trials: Trial 29,182 Trial 33,44 Trial 186,183 Trial 318184 and Trial 136,180 of  patients with mild, moderate, unspecified (two trials), and moderate to severe acne. Trial 136 was

a three-arm trial. Trials 29 and 33 both used complementary placebos (topical and oral) to ensure

patient blinding. Trial 186 suffered from major losses to followup.

	Trial 186 resulted in equal numbers, and statistically nonsignificant differences, in many

lesion-based outcomes, ranging from comedones to cysts. In Trial 136, papule and pustule counts

were reduced equally, but physicians rated clindamycin as leading to statistically significantly

greater improvement than tetracycline, while patients rated themselves as improved to the same

degree. In Trial 33, there were statistically significant changes within each group. Clindamycin

conferred a statistically significantly greater decrease in inflammatory lesions at 8 weeks, but

conferred no advantage in Trial 29 at 4 weeks. Overall changes, as determined by patients or

physicians, were better in the tetracycline group, although P-values were not provided.  In Trial

318, there was no statistically significant difference in pustules counts.

	Side effects included diarrhea in both groups (Trial 33) or erythema (Trial 186), for a total of

four cases.

H.08.03   –	Tetracycline (oral) vs. Erythromycin (topical)

	There was one medium trial, Trial 279,185 of patients with moderate to severe acne. Overall assessment was that patients were improved in both arms, with no statistically significant

difference. Counts of many lesion types were presented. For many of them, within-arm

improvement was statistically significant, but the difference between arms was not statistically

significant. 

	Two patients withdrew because of adverse reactions.

H.08.04   –	Tetracycline (oral) vs.Tetracycline (topical)

	There were two small trials and one medium trial, Trial 10,80 Trial 23,81 and Trial 313,83 all three-arm trials of mild to moderately affected patients. Trial 23 reported evidence of randomization but had a pharmaceutical-company as co-author, and Trial 313 was generalizable

to the local population.

	Only relative improvement outcomes were provided. Patients improved in all arms, with a

statistically significant difference between oral and topical treatment in only one trial, Trial 23.  

No side effect data were reported.

H.08.045  –	Tetracycline (oral)/Tetracycline (topical) vs. Tetracycline (oral)

	There was one medium study, Trial 40,82 of young adults and late adolescents of undetermined severity. Severity decreased in both arms, but comparison P-values were not

provided. Gastrointestinal symptoms were apparently comparable; P-values were not provided.

H.08.05 –		Tetracycline (oral) vs. Azelaic Acid

	There was one small trial, Trial 22,186 and two large trials, Trial 167187 and Trial 166,187 of  patients with mild through severe acne. Trials 167 and 166 were adequately randomized. Trial 22

suffered from major losses to followup.

	Relative improvement was “excellent” or “good” in the majority of patients in both arms in

Trial 167 and Trial 166. Lesion counts were reduced in both arms in Trial 22 and Trial 166. Only

the former, the smallest trial, found a statistically significant difference between the treatments in

one comparison of lesion counts, out of a total of nine count-based outcomes.

	A single case of abdominal pain, in Trial 22, was reported.

H.08.055  –	Tetracycline (oral) vs. Minocycline (oral)

	See H.05.04.

H.08.06   –	Tetracycline (oral) vs. Meclocycline/Sulfosalicylate (topical)

	There was one medium trial, Trial 164,188 of young adults with mild to moderate acne. Of the many outcomes assessed, both treatments reduced all lesions about 70 percent. Tetracycline was

statistically significantly better in treating open comedones. Otherwise, the reduction was the

same in the two groups. The authors report that there were no side effects, but they provide no

specific data.

H.08.07   –	Tetracycline (oral) vs. Clindamycin (oral)

	See H.01.02.

H.08.08   –	Tetracycline (oral) vs. Tetracycline (oral)

	There were two medium trials that compared different regimens of tetracycline. Trial 212,189 where acne severity could not be discerned, compared tetracycline sustained release 250 mg once

daily with tetracycline 250 mg twice daily in young adults. The trial was limited by major losses to followup. Trial 317,190 of severely affected patients, compared tetracycline 250 mg four times daily with a similar tetracyline regimen plus proteolytic enzymes in severely affected patients.

	In Trial 212, two-thirds of patients were improved at 12 weeks, but there was no statistically

significant difference between treatments. In Trial 317, patients were much improved in both

groups at 12 weeks, but with no statistically significant difference between treatments. 

	Side effects were few (diarrhea [1] and sore mouth [1]) in Trial 212.

H.08.085  –	Tetracycline/Sodium Novobiocin (oral) vs. Inert (oral)

	There was one small two-arm trial, Trial 299,191of adolescents and young adults with moderate to severe acne. Blinding is documented and there were no losses to followup, although

arms were not comparable. Patients treated with anti-bacterial combination reported greater

overall improvement (and statistically significantly more) than patients treated with placebo. Side

effects data were not provided.

H.08.09   –	Tetracycline (oral) vs. Isotretinoin (oral)

	See K.02.03.

H.08.10   –	Tetracycline (oral) vs. Cyproterone/Ethinyl Estradiol (oral)

	See M.01.03.

H.08.11   –	Tetracycline (oral) vs. Gugulipid (oral)

	See N.01.02.

H.08.12   –	Tetracycline (oral) vs. Ocimum Basilicum (topical)

	See N.01.04.

H.08.125  –	Tetracylcine (oral) vs. Ibuprofen/Tetracycline (oral)

	See N.06.045.

H.08.13   –	Tetracycline (oral) vs. Zinc (oral)

	See N.07.03.

H.08.135  –	Tetracycline (oral) vs. Zinc/Erythromycin (oral)

	See N.08.04.

H.08.14   –	Tetracycline (oral)/Povidone-iodine (topical) vs. Tetracycline (oral)/ Vehicle (topical)

	There was one small trial, Trial 236,29 of moderately to severely affected patients notable by the absence of treatment information regarding povidone-iodine and by major losses to followup.

No comparison statistics were provided, but outcomes were comparable. There were zero side

effects reported.

H.09    –		Other Anti-bacterial (oral)

H.09.01  –	Dapsone (oral) vs. Placebo (oral) 

	Although dapsone is an anti-microbial, it does not have activity against P. acnes.

	There was one small trial, Trial 293.192 There were no losses to followup. There was a statistically significant difference in severity change favoring dapsone. This is one of the few

trials to stratify results by gender. The results were about the same for each sex, although P-

values were not reported. Side effects were numerically greater in dapsone, but not statistically

significantly different.

H.09.02   –	Phenethicillin (oral) vs. Placebo (oral)

	There was one medium trial, Trial 312,151 of mixed acne severity, where patients were not blinded. Physicians’ assessment of overall change was that most patients were judged to be

unchanged, and overall change for the treatment arm was not statistically significantly different

from control.

H.09.03   –	Phenethicillin (oral ) vs. Demethylchlortetracycline (oral)

	See H.02.02.

H.09.04   –	Sodium Fusidate (oral) vs. Sodium Fusidate (topical)

	There was one medium trial, Trial 344,193 of all levels of acne severity. Treatment assignment was not properly randomized and patients and care provider were not blinded. There was a

blinded outcome assessment made, however. The numbers in each improvement category were

similar, although no between-arm P-values were provided. There was about a 10 percent side

effect rate in the oral group and zero percent in the topical, but numbers were small.

H.09.05   –	Tetracycline/Novobiocin (oral) vs. Placebo (oral)

	There were two trials: one small trial, Trial 279,191 and one small seven-arm trial, Trial 340,161 with treatment between 6 and 18 months; both trials had patients with moderate to severe acne. There were no losses to followup in Trial 279 and there was well-executed blinding. On

physicians’ evaluation, the antibiotic group improved statistically significantly more than the

placebo group. Side effects were comparable but infrequent. In Trial 340, the outcome was inter-

treatment comparison against placebo. The tetracycline-novobiocin arm had the fewest number

of patients rating it as the preferred treatment.

Class I.	Anti-bacterial (oral)/Keratolytic (topical) 

I.01	  –		Cotrimoxazole/Sulfur/Resorcinol

I.01.01   –		Cotrimoxazole (oral)/Sulfur/Resorcinol vs. Cotrimoxazole (oral)/Placebo

	There was one large multi-center, three-arm trial, Trial 126 (N=211).194 Methodological issues included 22 percent of enrolled patients not randomized, subjects’ baseline acne severity

not ascertainable, major losses to followup, and patients and outcome assessors were not blinded.

There were many outcomes, including severity assessments and lesion counts, showing no

statistically significant difference between the groups. Erythema appeared more frequent (about

one-third) in the treatment group, but a P-value was not provided.

I.01.02.  –		Cotrimoxazole (oral)/Sulfur/Resorcinol vs. Cotrimoxazole (oral)/ Tretinoin 

	There was one large multi-center, three-arm trial, Trial 126 (N=211).194 Methodological issues included 22 percent of enrolled patients not randomized, subjects’ baseline acne severity

not ascertainable, major losses to followup, and patients and outcome assessors not blinded. All

efficacy differences (severity change and lesion counts) had P-values of 0.001. Desquamation

and erythema appeared comparable, but P-values were not provided.

I.02	  –		Tetracycline (oral)/Keratolytic

I.02.01   –		Tetracycline (oral)/Sulfur/Salicylic Acid/Polyethylene Scrub vs. Tretinoin/Benzoyl Peroxide/Water Avoidance

	There was one medium three-arm trial, Trial 323,195 that included many patients of a narrow age range, but a wide range of acne severity. The report shows evidence of good randomization,

blinding, and no losses to followup. There were many efficacy outcomes. The

tetracycline/keratolytic combination achieved significant within-arm P-values for total lesion

change, for comedo change, and for papule+pustule change. The tretinoin/keratolytic

combination achieved a significant within-arm P-value for comedo change. The between-arm P-

values were not significant, however. Ratings of side effects were low, but standard deviations

were not provided to enable a comparison between the arms.

Class J.	Anti-bacterial (oral)/Retinoid (topical)

J.01.01   –	Cotrimoxazole (oral)/Tretinoin (topical) vs. Cotrimoxazole (oral)/ Placebo (topical)

	There was one large multi-center, three-arm trial, Trial 126 (N=211),194 where acne severity cannot be categorized. Only 78 percent of recruited patients were enrolled, patients were not

blinded, outcome assessor was not blinded, and there were major losses to followup, as well as

other major protocol departures. The outcomes were discretized improvement in pustule counts

(statistically significant difference in favor of the combination therapy), in papule counts (not

statistically significant), and in severity (statistically significant). Side effects of erythema and

desquamation appear comparable in the two groups, although comparison statistics are not

provided.

J.01.02    –	Oxytetracycline (oral)/Vitamin A (topical) vs. Oxytetracycline (oral)/ Placebo (topical) vs. Vitamin A (topical)/Placebo (oral)

	There was one large multi-center, three-arm trial, Trial 57,196 where the subjects in arms were similar along many dimensions, but where there were major losses to followup (N=238). Most

patients were judged to have had 75-100 percent reduction in lesions, but P-values were not

reported. No comparison between arms reached statistical significance. Over two-thirds of

patients had local side effects in each group. The difference between arms is not statistically

significant.

J.01.03    –   	Tetracycline (oral)/Tretinoin (topical)/Emollient vs. Tetracycline (oral)/ Sulfur/Salicylic Acid/Polyethylene Scrub (topical) vs. Tretinoin/

Benzoyl Peroxide/Water

	There was one three-arm trial, Trial 323,195 that included many patients of a narrow age range, but a wide range of acne severity. The report shows evidence of good randomization,

blinding, and no losses to followup. All arms yielded changes in comedones and inflammatory

lesions of about 40 percent. The tretinoin/benzoyl peroxide arm resulted in decreases that were

statistically significantly larger. No side effects data were reported.

Class K.	Retinoid (oral)

K.01    –	Alitretinoin

K.01.01  –	Alitretinoin (oral) vs. Isotretinoin (oral)

	See K.02.04.

K.02    –		Isotretinoin 

	The teratogenic effect of isotretinoin is well known. None of the trials reviewed reported

births or birth defects. The trials excluded women or women who were pregnant or lactating, and

the trials reported contraceptive precautions. 

K.02.01  –	Isotretinoin (oral) vs. Placebo (oral)

	There was one small trial, Trial 269,197 that compared isotretinoin to placebo in patients with severe acne. Patients in the isotretinoin arm had a decrease in the number of cysts while patients

in the placebo arm had an increase in the number of cysts. This difference was statistically

significant. Side effects of cheilitis (1), dermatitis (1), and arthralgia (1) were reported in the

treatment arm.

K.02.02   –	Isotretinoin (oral) vs. Dapsone (oral)

	There was one small trial, Trial 276,198 which evaluated males with severe acne. In the isotretinoin arm, there was statistically significant overall change as rated by the patient on a

visual analogue scale beginning at 4 weeks of followup. Improvement in overall severity was

statistically significant beginning at week 8. Statistically significant improvement in chest/back

and face/neck were seen at week 16. All of these improvements persisted post-therapy. In the

dapsone arm, there was some statistically significant improvement over baseline as rated by the

patient in overall change and in face/neck count beginning at week 16. The isotretinoin arm had

more improvement than the dapsone arm in the post-therapy face/neck count, though P-values for

comparison between the treatment arms were not always provided. Other comparisons such as

16-week chest/back lesion count and total severity were not statistically significant. Cheilitis was

reported in 17 patients in the isotretinoin arm but none in the dapsone arm.

K.02.03   –	Isotretinoin (oral) vs. Tetracycline Hydrochloride (oral)

	There was one small trial, Trial 206,199 that evaluated patients with severe acne. This trial had major losses to followup. Patients in both treatment arms had improvement in the number of

cysts, cyst diameter, and comedones and pustules present, though no P-values were provided.

There were no statistically significant differences between the arms at 12 weeks; however, at

post-therapy followup, the patients in the isotretinoin arm had statistically significantly greater

improvement in cyst count, cyst diameter, and comedo and pustule count than patients in the

tetracycline arm. More local side effects were reported in the isotretinoin arm (70 vs. 11) and

more systemic side effects were reported in the isotretinoin arm (9 vs. 6), although no P-values

were provided.

K.02.04   –	Isotretinoin (oral) vs. Alitretinoin (oral)

		There was one small trial, Trial 127.200 In this trial, males received either alitretinoin or isotretinoin. Patients in both treatment arms reported side effects including abdominal pain or diarrhea (2 vs. 0), dryness of various membranes (20 vs. 23), headache (5 vs. 1) and red face (6

vs. 10). Overall, similar numbers of side effects were reported, although no P-values were

provided.

K.02.05   –	Isotretinoin vs. Etretinate

	There is one medium trial, Trial 130,201 of patients with severe acne.  While patients in both arms showed improvement, isotretinoin was statistically significantly more effective in reducing

inflammatory nodules at the end of treatment and 8 weeks of post-therapy than was etretinate.

Improvement for both treatments was notable on the face more than on the chest or back.  Side

effects of cheilitis were noted in all patients, and conjunctival injection was noted in 25 percent

of patients in each treatment group.

K.02.06   –	Isotretinoin (oral) vs. Isotretinoin (oral)

	There were six trials. Trial 5202 was a small trial of patients with severe acne, while Trial 185203 was a medium trial of patients with moderate acne, Trial 332204 was a medium trial of patients with severe acne, and Trial 320205 was a large multi-center trial of patients with severe acne. Trial 106206 was a small three-arm trial as was Trial 190.207 Examined together, these  trials evaluate isotretinoin at different doses, comparing 0.1mg/kg to 0.3, 0.5 and 1.0 mg/kg, and

comparing 0.3 to 0.5 and 0.5 to 1.0 mg/kg. In Trials 5, 185, and 332, the higher dose of

isotretinoin was associated with either more patients rated as “very good” or “good”

improvement, or with greater percent change in non-inflammatory lesions. However, in Trials

320 and 332, there was statistically significant improvement in all treatment groups, with no

significant differences in improvement between the different dosage groups. 

	In Trials 5, 106, 185, and 332, the higher doses were also associated with more side effects,

with cheilitis, facial dermatitis, desquamation and epistaxis being the most common complaints.

Taken together, these side effects were reported at least 14 times per arm in Trial 5. In Trial 320,

there were minor differences in the side effect profiles at different doses, but 42 percent of

patients given the lowest dose of 0.1 mg/kg/day required treatment. Similarly, a dose response for

side effects was suggested by Trial 106, but P-values were not provided. More systemic side

effects were noted at the 1.0 mg/kg dose. No P-values were presented.

K.03 	   –	Other Retinoid

K.03.01   –	Vitamin A (oral) vs. Placebo (oral)

	There was one medium trial, Trial 12,208 comparing vitamin A to placebo. Similar numbers of patients were rated “improved” (34 vs. 33) and “no change” (23 vs.17), with more patients being identified as “worse” in the placebo arm (3 vs. 22). No P-values were presented. No side effect data were presented.

K.03.02   –	Vitamin A/Zinc Sulfate (oral)

	There was one small four-arm trial, Trial 233,209 that evaluated vitamin A palmitate (oral), zinc sulfate (oral), their combination, and placebo in patients with moderate to severe acne.

Severity change was numerically similar in the vehicle and vitamin A groups, and greater (and

equal) in the zinc and combination group. No comparison statistics were provided. There were no

patients with dry skin in the vehicle and vitamin A group, and four each in the other two groups.

No comparison P-values were available.

Class L.	Retinoid (oral)/Keratolytic

	No comparisons are available.

Class M.	Anti-androgen

M.01	   –	Cyproterone

M.01.01  –	Cyproterone (topical) vs. Vehicle (topical)

	There was one small trial, Trial 141.210 Women with mild and moderate acne were evaluated. Neither the patient nor the outcome assessor was blinded. At 12 weeks, there was improvement

in the face severity, total lesion count and total lesion percent change compared to baseline but

no within-arm P-values were provided. There were statistically significant differences between

the treatment arm and the vehicle arm in terms of severity change and total lesions percent

change. No side effect data were provided.

M.01.02  –	Cyproterone/Ethinyl Estradiol (oral) vs. Minocycline Hydrochloride (oral)

	There was one medium trial, Trial 245,211 that evaluated women with mild or moderate acne. This trial was not blinded and had major losses to followup. Both treatments demonstrated

statistically significant reductions in the papule, pustule, and comedo mean counts at week 24

compared to baseline. No P-values for between group comparisons were provided. Side effects of

nausea, vomiting, giddiness, bleeding problems, and headaches were reported in both arms. In

addition, diarrhea, heartburn, and depression were reported in the minocycline arm. Differences

in the number of patients reporting side effects were not statistically significant.

M.01.03 –		Cyproterone/Ethinyl Estradiol (oral) vs. Tetracycline/Placebo (oral) vs. Cyproterone/Ethinyl Estradiol/Tetracycline (oral)

	There was one medium trial of female patients, Trial 137,212 a three-arm trial of cyproterone/ethinyl estradiol with tetracycline or the tetracycline placebo versus tetracycline

(with placebo for birth control pills). This trial had major losses to followup. In all arms, there were statistically significant improvements in the inflammatory lesion change, total severity

change, and face severity change at all time points. The improvement in non-inflammatory

lesions was numerically different, but not statistically significantly different. In the tetracycline

arm, there was statistically significant improvement in all of the outcome measures over baseline.

At week 24, there was no statistically significant difference between the arms in terms of

inflammatory lesion change, but the cyproterone/ethinyl estradiol arm shows statistically

significantly greater improvement in total severity. Side effects of hypertension (1) and

dysmenorrhea (1) were reported in the cyproterone/ethinyl estradiol arm. Side effects of chest

pain (1), headache (1), menstrual irregularity (1), and breast tenderness (1) were reported in the

cyproterone/ethinyl estradiol/tetracycline arm. No side effects were reported in the tetracycline

arm.

M.01.04   –	Cyproterone/Ethinyl Estradiol (0.035mg) (oral) vs. Cyproterone (topical)

	There was one small trial, Trial 141.210 Women with mild and moderate acne were evaluated. Neither the patient nor the outcome assessor was blinded. At week 12, both arms showed

improvement in face severity, total lesion count and percent change, although no P-values were

provided for comparison to baseline. There were statistically significant differences between the

topical cyproterone arm and the cyproterone/ethinyl estradiol arm in terms of total severity

change and Leeds severity score, with the topical cyproterone showing greater improvement.

However, there were no statistically significant differences between the arms in total lesion

count. No side effect data were provided.

M.01.05   –	Cyproterone/Ethinyl Estradiol (0.05mg) (oral) vs. Cyproterone/Ethinyl Estradiol (0.035mg) (oral)

	There were three medium and large trials which evaluated the combination of

cyproterone/ethinyl estradiol in various strengths in women: Trial 48,213  Trial 66,214 and Trial 117.215  The s tudrieals had a total sample size of 302 patients and evaluated the combination of 2 mg cyproterone with 0.035 mg vs. 0.050 mg of ethinyl estradiol in women with moderate to severe acne. The trials demonstrated statistically

significant improvement in severity within both arms with respect to baseline. No statistically

significant difference between the arms was found. Systemic side effects were noted once in 22

patients in each arm, and more than once in at least 10 patients in each arm, although no P-values

were provided.

M.01.06   –	Cyproterone (2mg)/Ethinyl Estradiol (oral) vs. Cyproterone (0.05mg)/ Ethinyl Estradiol (oral)

	There was one medium trial, Trial 237,216 of female patients with mild to moderate acne. The trial demonstrated statistically significant improvement in face papule count, face severity, and

total severity by week 26. There was no numerical difference between the two arms in papule or

nodule count, but there was a numerical difference in face severity, with the high cyproterone dose demonstrating greater improvement. P-values between the two arms, however, were not

available and could not be calculated.

M.01.07   –	Cyproterone/Ethinyl Estradiol (oral) vs. Desogestrel/Ethinyl Estradiol (oral)

	There was one small trial, Trial 55,217 and two large trials, Trial 87218 and Trial 103219 (all women), some with mild acne (Trial 55) and the remainder unspecified, that compared

cyproterone/ethinyl estradiol to desogestrel/ethinyl estradiol at different doses. In Trial 55, there

was no blinding. The trial was administered at two sites. Trial 87 had major losses to followup.

In both trials, both treatment arms demonstrate some improvement in severity of acne. By long

term followup, this improvement is statistically significant for both cyproterone sites in the

cyproterone arm, but only for one site in the desogestrel arm. P-values were not provided in Trial

87. Comparing the two treatment arms, there was statistically greater improvement in the

cyproterone arm at one site, but no difference between the arms at the other site or in Trial 87.

No side effect data were presented.

M.01.08   –	Cyproterone/Ethinyl Estradiol (oral) vs. Levonorgestrel/Ethinyl Estradiol (oral)

	There was one large trial of female patients with unspecified acne severity, Trial 48213 (N=133). It compared cyproterone with low-dose and high-dose ethinyl estradiol to levonorgestrel/ethinyl estradiol. Results show that both cyproterone/ethinyl estradiol and

levonorgestrel/ethinyl estradiol improved total lesion percent change, but no P-values were given

in the comparison to baseline. The cyproterone/ethinyl estradiol arm had a statistically

significantly greater decrease in total lesion change at 16 weeks than the levonorgestrel/ethinyl

estradiol arm, but there was no statistically significant difference between the arms at 24 weeks.

No side effect data were presented.

M.01.09   –	Cyproterone/Ethinyl Estradiol (oral) vs. Norethisterone/Ethinyl Estradiol (oral)

	There was one medium trial of women with moderate to severe acne, Trial 237.216 Comparison of cyproterone/ethinyl estradiol to norethisterone/ethinyl estradiol demonstrated

statistically significant reduction of face severity and total severity in both arms by week 26.

Papule count was only statistically significantly reduced in the cyproterone/ethinyl estradiol arm.

There were no statistically significant differences between the arms in nodule count or papule

count. There was statistically significantly more improvement in the norethisterone arm in total

severity and face severity. No side effect data were presented.

M.02	  –		Desogestrel/Ethinyl Estradiol

M.02.01  –	Desogestrel/Ethinyl Estradiol (oral) vs. Gestodene/Ethinyl Estradiol (oral)

	There was one trial, Trial 225,220 a small trial of patients with mild and moderate acne. This trial had limitations including lack of blinding and major losses to followup. Both treatments

showed statistically significant improvement in acne severity grade at 36 weeks compared to

baseline. The patients that received desogestrel/ethinyl estradiol had more improvement than

those in the gestodene/ethinyl estradiol arm, although no P-values were provided. Similar

numbers of patients reported systemic side effects in the desogestrel/ethinyl estradiol arm (6) and

in the gestodene/ethinyl estradiol arm (4).

M.02.02  –	Desogestrel/Ethinyl Estradiol (oral) vs. Levonorgestrel/Ethinyl Estradiol (oral)

	There were two trials. Trial 264221 was a small trial of women with mild and moderate acne. Trial 263222 was a medium trial. Trial 264 demonstrated statistically significant improvement in acne severity over baseline in both treatment arms, with the desogestrel arm having statistically

significantly greater improvement than the levonorgestrel arm. Similarly, in Trial 263 there were

patients in both arms who were rated “improved” at 24 weeks, but there were statistically

significantly more improved patients in the desogestrel arm. Side effects were reported in Trial

263. Two patients in the desogestrel arm and three patients in the levonorgestrel arm reported

irregular bleeding. Two patients in the desogestrel arm and four in the levonorgestrel arm

reported that their acne was worse and dropped out. While these numbers were similar, no P-

value was provided.

M.03	  –		Spironolactone

M.03.01  –	Spironolactone (oral) vs. Placebo (oral)

	There were three trials. One was a small four-arm trial, Trial 156,223 of patients with moderate to severe acne, limited by the absence of blinding. Results were stratified by gender. Women

seemed to have lower severity scores than men, but no comparison statistics were reported. The

second was a large cross-over trial, Trial 249,224 of 200 mg daily in women with mild-to- moderate acne (N=58 in each arm). The third was a very small five-arm trial, Trial 132,225 of four doses of spironolactone tested (50, 100, 150, and 200 mg daily) in a mixed-gender pool of

patients with severe acne. Trial 249 was weakened by major losses to followup. 

	In Trial 249, spironolactone provided greater improved lesion counts (75 percent vs. 20 percent), greater improvement in patients’ perceived severity (90 percent vs.10 percent) and in photography-based severity assessment (55 percent vs. 20 percent). There were side effects deemed “positive” by the authors (decreased oily skin and breast enlargement) as well. In Trial 132, the higher doses of spironolactone may have led to higher assessments of overall change,

but the numbers were very small.

	There was a high rate of menstrual irregularity in Trial 249 and about a 10 percent rate of

severe nausea, bad enough to lead to patient withdrawal; but the actual numbers are small. Trial

132 did not report any side effects.

M.04	  –		Other Anti-androgen 

M.04.01 –		Delta-0.2 percent Chlormadione (topical) vs. Vehicle (topical)

	There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side

effects were reported.

M.04.02 –		Delta-5 percent Chlormadione (topical) vs. Vehicle (topical)

	There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side

effects were reported.

M.04.03 –		Delta-5 percent Chlormadione (topical) vs. Delta-0.2 percent Chlormadione (topical)

	There was one small trial, Trial 2.226 There were no patients who had any change in their acne reported by either physician or patient, although no P-values were provided. No data on side

effects were reported.

M.04.04   –	16-Epiestriol-3-Allyl Ether (oral) vs. Placebo (oral)

	There was one large trial (N=134). Trial 19227 compared the synthetic estrogen 16-epiestriol- 3-allyl ether to placebo. After 12 weeks of treatment, there was no statistically significant

difference in acne severity between the treatment arm and the placebo arm, with similar numbers

of patients rated as “no change” (31 vs. 34), “improved” (19 vs. 26) and “marked improvement”

(16 vs. 8). Similar number of patients also reported improvement in oiliness in both groups.

M.04.05  –	Epiestriol (topical) vs. Vehicle (topical)

	There was one small split-face trial, Trial 295.228 After 12 weeks, more patients were termed “better” in terms of severity in the placebo arm than in the treatment arm, though no P-values

were provided. Both arms had the same number of patients rated as “worse” (7), “unchanged”

(18), and “improved” (19) in terms of overall change as rated by the physician at 12 weeks. No

side effect data were provided.

M.04.06  –	Inocoterone Acetate (topical) vs. Vehicle (topical)

	There was one large trial (N=153), Trial 213,229 that evaluated male patients with moderate acne. While there was no statistically significant difference in the inflammatory lesion count or

the comedo count between the treatment arm and the placebo arm at 4 weeks, there was a

statistically significantly greater decrease in the inflammatory lesion count at weeks 12 and 16 in

the treatment arm. There remained no statistically significant difference between the two arms in

terms of comedo count at 12 or 16 weeks. The number of inflammatory lesions decreased

steadily from baseline through week 16 in the treatment arm, but no P-values were provided for

within group comparison. Local reactions in the treatment arm included burning (32), stinging

(18), itching (10), redness (19), and peeling (27). There were no statistically significant

differences between the two arms with respect to the number of patients reporting local adverse

reactions. 

M.04.07   –	Levonorgestrel/Ethinyl Estradiol (oral) vs. Cyproterone/Ethinyl Estradiol (oral)

	See M.01.08.

M.04.08   –	Norethisterone/Placebo/Ethinyl Estradiol (oral) vs. Cyproterone/Ethinyl Estradiol (oral)

	See M.01.09.

M.04.09   –	Norgestimate/Ethinyl Estradiol (oral) vs. Placebo (oral)

	There were two large trials of women, Trial 218230 (moderate acne) and Trial 280 (mild to moderate acne).231 While Trial 218 had major losses to followup, it did demonstrate decreases in total lesions, comedo count, and inflammatory lesion count at 26 weeks compared to baseline

although no P-values were provided. The differences were statistically significant compared to

placebo. There was no statistically significant improvement in the number of nodules compared

to placebo. Similarly, Trial 280 demonstrated change in total lesion count, inflammatory lesions,

and comedones, although no P-value was provided for comparison to baseline. The percent

change, both in inflammatory lesions and in total lesions, was statistically significant compared

to placebo. Both trials demonstrate statistically significant overall change reported by both

investigator and patient. Trial 280 reported similar numbers of adverse events reported between

treatment arm and placebo arm, with 13 patients discontinuing therapy and 113 patients reporting

events in the treatments arm, and 5 patients discontinuing therapy and 119 other events reported

in the placebo arm. No P-values were presented.

M.04.10  –	Quinestradol (oral) vs. Placebo (oral)

	There was one medium trial of women with mild to moderate acne, Trial 248,232 with major losses to followup. After 8 weeks, patients in the treatment arm demonstrated a statistically significant decrease in the comedo count and total lesion count compared to baseline. However,

there were no statistically significant differences demonstrated between the treatment arm and the

placebo arm in terms of either outcome. No side effect data were presented.

M.04.11 –		Serum Gonadotropin (oral) vs. Placebo (oral)

	There was one small trial, Trial 271,233 a trial of patients with mild, moderate, and severe acne. In addition to serum gonadotropin (with unclear proposition of luteinizing hormone and/or

follicle stimulating hormone) or placebo, patients received ancillary treatments including

ultraviolet light and antibiotics. Similar numbers of patients were rated as “improved” (8 vs. 9),

“no change” (9 vs. 9), and “worse” (2 vs. 3) in the treatment and placebo arms after 12 weeks of

treatment, although no P-values were provided. No side effect data were presented.

Class N.	Other

N.01.01   –	Ayurvedic Remedies (oral)

	There was one medium trial, Trial 266,234 that compared three oral Indian ayurvedic remedies, sookshama triphala, shankhabhasma vah, and sunder vati, with placebo and the

keratolytic, thiostanin. The trial is notable in that the investigators used a government agency to

assure the constituents of the treatments. Only the effectiveness with respect to baseline of sunder

vati reached statistical significance for non-inflammatory and inflammatory lesions. No data on

side effects were reported.

N.01.02   –	Gugulipid (oral) vs. Tetracycline (oral)

	There was one small trial, Trial 325,235 of severely affected late adolescents/young adults. Effect of both treatments was to reduce counts of inflammatory and non-inflammatory lesions,

but within-group P-values are not provided. Differences between groups were not statistically

significant, except for severity change at 12 weeks. No data were provided on side effects.

N.01.03   –	Isolutrol (topical) vs. Benzoyl Peroxide (topical)

	There was one medium trial, Trial 94,236 of late adolescents with mild to moderate acne. Based on group data, inflammatory and non-inflammatory lesions were reduced statistically

significantly in the benzoyl peroxide group; only non-inflammatory counts in the isolutrol were

statistically significantly reduced, and only at 12 weeks. Local side effects (burning, dryness,

erythema, pruritus, and scaling) appeared in about half the benzoyl peroxide patients and in only

about one-fifth of the isolutrol group. 

N.01.04   –	Ocimum Basilicum (topical) vs. Tetracycline (oral)

	There was one small trial, Trial 17,237 with patients of a wide age and severity spectrum, where design was weakened by the absence of blinding and by major losses to followup. For the single outcome, severity change, comparison P-values were not provided, although the numbers

appear comparable. There were no data on side effects.

N.01.05   –	Tea Tree Oil (topical) vs. Benzoyl Peroxide (topical)

	There was one large trial (N=124), Trial 18,238 of late adolescents with moderate acne, notable for good blinding and the absence of losses to followup, but weakened by absence of

randomization. Both treatments were effective with respect to baseline. Benzoyl peroxide bested

tea tree oil at 4 and at 12 weeks on inflammatory, but not non-inflammatory, lesions. The rate of

side effects was about 50 percent for tea tree oil and 80 percent for benzoyl peroxide, with large

numbers and a statistically significant difference.

N.02	   –	Anti-inflammatory

N.02.01   –	Clobetasol (topical) vs. Vehicle (topical)

	There was one very small, split-face trial, Trial 175,239 of patients with moderate to severe acne. No dose information was provided. Change in severity appears better in clobetasol, but

between-group P-value was not significant. 

N.02.02   –	Hydrocortisone/Neomycin/Sulfur/Resorcinol

	There were two small multi-arm trials, Trial 28779 and Trial 288,79 both with little methodological information, and uncertain duration. These trials examined different

combinations of the components of this treatment. Each component, and their aggregate, yielded

a subjective “improved” rating in about half the patients in each arm. Sulfur and resorcinol

resulted in itching or erythema in more patients than any other treatment, but there were few

patients with any side effects.

N.02.03   –	Hydrocortisone vs. Hydrocortisone/Sulfur (topical)

	There was one medium multi-arm trial, Trial 288,79 with little methodological information. In the single efficacy outcome, physician’s assessment of overall change, about half the patients

improved in these two arms. No comparison P-values were provided. There were few side

effects, but numbers were too small for comparison.

N.02.04   –	Methylprednisolone/Neomycin (topical) vs. Vehicle (topical)

	There was one large multi-center, three-arm trial (N=776), Trial 228,40 that amalgamated several double-blind trials (five trials involving dermatologists and seven trials involving general

practice centers) so that patients’ severity and many other details are not determinable and arm

sizes are not equal. Physicians’ assessment of overall change was dramatically different: 84 percent improvement versus 50 percent in the vehicle group; P = 0.001. No side effect data were provided.

N.02.05   –	Methylprednisolone/Neomycin/Sulfur (topical) vs. Vehicle (topical)

	There was one large trial, Trial 102,240 of patients with unstated acne severity and no other patient data, and one medium trial, Trial 346,241 of patients with comedonal acne. In Trial 102, for the single outcome “overall change,” the difference was statistically significant in favor of the

treatment. In Trial 346, active treatment was statistically significantly better as regards patient

acceptance and physician evaluation.

N.02.06    –	Methylprednisolone/Neomycin (topical) vs. Aluminum Chlorhydroxide/Sulfur (topical) 

	There was one large multi-center, three-arm report, Trial 228,40 that amalgamated several double-blind trials   (five trials involving dermatologists and seven trials involving general

practice centers) so that patients’ severity and many other details are not determinable and arm

sizes are not equal. There was also one medium trial, Trial 347,241 of patients with comedonal acne.  The steroid/anti-bacterial treatment gave statistically significantly better results in Trial

228 but gave equal results in Trial 347.

N.02.07  –	Methylprednisolone/Neomycin (topical) vs. Tretinoin (topical) 

	See E.05.08.

N.03    –		Biologicals

N.03.01  –	Gamma Globulin (parenteral) vs. Placebo (parenteral)

	There was one small trial, Trial 189,242 of subjects with wide age range and severity spectrum. Patients received variable numbers of injections, and there is no information on when outcomes

were assessed. The outcomes were numerically similar.

N.03.02   –	Fractionated Dialyzable (topical) vs. Unfractionated (topical) Transfer Factor vs. Saline 

	There was one small trial, Trial 15,243 of severely affected young adults. Relative improvement was similar in all groups, although P-values were not provided; about half the

patients were not improved in any group.

N.03.03   –	Staphylococcal Toxoid (topical) vs. Vehicle (topical)

	There was one small trial, Trial 222,244 of Royal Air Force males with a wide spectrum of acne severity, although results were stratified by acne severity. Numbers appear similar, although

no P-values were provided. Adverse reactions were reported only for week 1 of therapy.

N.04    –	 	Chloramphenicol/Hydrocortisone (topical)

N.04.01  –	Chloramphenicol/Hydrocortisone (topical) vs. Vehicle (topical)

	There was one small trial, Trial 297,245 of patients with mild to moderate acne. A  pharmaceutical employee was a co-author. A number of subjective assessments, by patients and

by physicians, and objective severity score yielded statistically significant differences in favor of

the combination treatment. Statistically significantly more patients withdrew from vehicle

treatment, presumably because of lack of efficacy. No side effects data were reported.

N.04.02   –	Chloramphenicol/Hydrocortisone/Sulfur/Buttoxethyl Nicotinate (topical) vs. Vehicle (topical)

	There was one large cross-over trial (N=120), Trial 224,246 of patients with the full spectrum of acne severity. The data show that patients were blinded, but there were major losses to

followup and the trial staff was not blinded. The combination was statistically significantly more

effective in reducing comedones, but not inflammatory lesions. Side effects (itchiness/dryness)

were few and comparable.

N.04.03   –	Chloramphenicol/Hydrocortisone/Sulfur (topical) vs. Chloramphenicol/Sulfur (topical)

	There was one medium trial, Trial 142,247 of patients with mild to moderate acne. Pharmaceutical employee was first author. Severity, improvement, and lesion count change were

the same. No side effect data were reported. 

N.04.04   –	Chloramphenicol/Hydrocortisone/Sulfur (topical) vs. Hydrocortisone/Sulfur (topical)

	There was one small two-center trial, Trial 115,248 where acne severity cannot be determined. The trial was randomized; pharmaceutical employee was co-author. Both treatments led to

statistically significant improvements in severity scores. The combination with chloramphenicol

yielded a statistically significantly greater improvement at 4 weeks, but the difference became

statistically nonsignificant at 12 weeks. Side effects (irritation and poor cosmesis) were few and

numerically similar.

N.04.05   –	Chloramphenicol/Hydrocortisone/Sulfur (topical) vs. Benzoyl Peroxide (topical)

	There was one small matched-control trial, Trial 75,249 of late adolescents with moderate acne. There were no losses to followup but degree of blinding is not clear, since the treatment

regimen (frequency) may have been different for the two arms. Both treatments led to statistically

significant improvements in severity and lesion count outcomes for inflammatory and non- inflammatory lesions. The differences between the treatments, however, did not reach statistical

significance. Side effects (erythema or scaling leading to treatment reduction) were about 10

percent in each group, but there was no statistically significant difference between the arms.

N.04.06    –	Chloramphenicol/Hydrocortisone (topical) vs. Tretinoin (topical)

	See E.05.09.

N.05	  –		Procedures

N.05.01 –		Grenz rays vs. Sham rays

	There were five trials: Trial 138,70 Trial 139,70 Trial 179,250 Trial 180,250 and Trial 350.251 Including multi-arm Trial 350 of severely affected patients, these were all split-face trials, but the

baseline characteristics were not made explicitly, and not all were randomized; there were major

losses to followup in one trial (Trial 139), and in two trials, outcome assessments were biased in

favor of radiotherapy (Trial 138, Trial 139). The total irradiated doses differed across the trials.

In two trials (Trial 138, Trial 139), the results favored Grenz rays (also called bucky rays), although no comparison P-values were provided, while in Trials 179 and 180, the numbers

appear equivalent. In Trial 350, hexachlorophene added to the Grenz rays led to numerically

greater severity improvement, although the authors did not report comparison statistics.

N.05.02   –	Comedo Extraction (cheeks/forehead) vs. Comedo Extraction  (forehead) vs. Untreated

	There was one small and one medium split-face trial, Trial 215252 and Trial 216,252 of patients of unknown acne severity and unknown gender. The second trial lists its ages (14-18 years). A

serious concern is that “some patients” were offered or were taking oral anti-bacterials at the

same time. No P-values were reported; our calculated one shows a nonstatistically significant

relationship.

N.05.03   –	Fulguration vs. Tretinoin (topical)

	There was one very small split-face trial, Trial 31,253 of patients with closed comedonal acne.  There was a statistically significantly greater improvement on the side of face treated with

fulguration than that by tretinoin. There were no data on side effects.

N.05.04   –	Fulguration vs. Electrocautery

	There was one very small split-face trial, Trial 32,253 of patients with closed comedonal acne. There were statistically significant improvements for large, but not for small, lesions.  The

differences in qualitative improvement and patients’ preferences were not statistically significant.

Three patients out of 15 total withdrew from the trial because of hypopigmentation or discomfort.

N.06	  –		Miscellaneous

N.06.01  –	Cimetidine

	There was one small four-arm trial, Trial 156,223 of patients with moderate to severe acne, weakened by the absence of blinding. Results were stratified by gender. Women seem to have

lower severity scores than men, but no comparison statistics were reported. 

N.06.02 –		Contingent Contract/Benzoyl Peroxide vs. Non-contingent Contract/Benzoyl Peroxide vs. Self-monitoring/Benzoyl Peroxide

	There was one small multi-arm trial, Trial 109,254 of patients with moderate acne, testing these different motivating techniques. Group-based total lesion counts were statistically

significantly decreased in all groups, and statistically significantly decreased with respect to the

no-treatment group. There were no reported statistical comparisons, however, among the

different interventions.

N.06.03   –	Group Therapy vs. Relaxation Therapy/Erythromycin/Benzoyl Peroxide (topical) vs. Erythromycin/Benzoyl Peroxide (topical) 

	There was one trial, Trial 172,142 a three-arm, matched-control trial of paid adults (mostly women), where the erythromycin/benzoyl peroxide group was a second set of observational

controls that received dermatology care in clinic but no other intervention. The relaxation group,

that included biofeedback and erythromycin/benzoyl peroxide, had the best outcome (P-value

across three groups, 0.01), both at the end of therapy and after cessation of treatment. 

N.06.04 –		Hydrochlorthiazide (oral) vs. Inert (oral)

	There were two trials, Trial 178255 and Trial 284.256  The first was a cross-over trial of women with peri-menstrual acne exacerbation, limited by major losses to followup. The second included

children as young as 8, was not randomized, and was not blinded. 

	Overall severity was either unchanged or even worse in the hydrochlorthiazide arms,

although no comparison P-values were reported. Side effects were numerically similar to those of

inert treatment in Trial 284.

N.06.045  –	Ibuprofen/Tetracylcine (oral) vs. Iinert (oral)

	There was one small two-arm trial, Trial 349,181 of young adults with mild to moderate acne. The arms were ibuprofen/tetracycline, tetracycline, ibuprofen, placebo. (Each arm had

appropriate placebo to make two medications for each patient.) Patient blinding was documented,

but physicians were not. At 8 weeks, total change was statistically significantly greater for the

combination over the other three arms.  While the change in single-treatment arms was greater than in placebo arm, P-values were not provided for those comparisons. Side effects data were

not provided.

N.06.05   –	Tolbutamide (oral) vs. Vehicle (oral)

	There was one small trial, Trial 110,257 of moderately affected patients, where subjects were not randomized. Dose information was not provided. P-values were not provided, but outcomes

appear the same in both groups.

N.07	  –		Zinc

N.07.01   –	Zinc (topical) vs. Vehicle (topical)

	There was one small trial, Trial 64,258 where subjects had mild to moderate acne. Severity was not improved any more over vehicle, while side effects (irritancy) were statistically

significantly greater in the zinc group.

N.07.02   –	Zinc (oral) vs. Inert (oral)

	There were nine trials: four small, Trial 3,259 Trial 259,260 Trial 211,261 and Trial 342262; four medium, Trial 91,263 Trial 133,264 Trial 336,265 Trial 341266; and one large, Trial 163.267  Three trials (Trial 91, Trial 163, and Trial 259) were multi-center. The trials were mostly of moderately

affected patients, but included mild to severe. Three trials had major losses to followup (Trial

259, Trial 341, and Trial 342); one had pharmaceutical employee co-authors (Trial 133). One

trial, Trial 133, is notable for documenting inter-rater reliability (between 0.54 and 0.68). The

doses across the trials are comparable, usually 200 mg (45 mg elemental zinc), but ranging from

137 mg to 600 mg.

	Out of 46 efficacy outcomes, including severity, lesion count, and photograph-based counts,

8 differences reached statistical significance, all in favor of zinc. The authors reported a range of

side effects: nausea, diarrhea, oiliness, irritancy. There were few reported comparison statistics,

and none was significant.

N.07.03   –	Zinc (oral) vs. Tetracycline (oral)

	There were two small trials, Trial 74268 and Trial 232,186 of patients with moderate to severe acne. One trial (Trial 74), comparing zinc against tetracycline, had no patient blinding, while the

other one (Trial 232), comparing zinc against oxytetracycline, had no losses to followup.

	Out of multiple outcomes, only one yielded a statistically significant difference: In Trial 74,

severity was improved more in the tetracycline arm. There were no side effects data.

N.08	 –		Zinc/Erythromycin

N.08.01 –		Zinc/Erythromycin (topical) vs. Vehicle (topical)

	There were three trials. Trial 108269 was a medium four-arm trial of males, 18-26 years old, with comedonal acne, that compared zinc/erythromycin gel and lotion against tetracycline and

against placebo, and was notable for its explicit procedure to blind the participant. There was one

medium trial, Trial 301,270 of females with moderate acne with major losses to followup, non- comparable arms, and unintended cross-overs from placebo to treatment group. Trial 321277 was a small two-arm trial of patients with mild to moderate acne that documented randomization and

had no losses to followup, but had inconsistent ascertainment across arms.

	In Trial 301, the combination was statistically significantly better than placebo for papules at 6 and 12 weeks. In Trial 321, there was statistically significant, and large, difference in

inflammatory change with respect to baseline at 10 weeks. In Trial 108, the statistically

significant results were that, in terms of severity, gel was more effective than lotion, which was

as effective as tetracycline, and both were more effective than placebo. In terms of papules, the

placebo fared poorer than the other three arms. No data on side effect events were reported.

N.08.02 –		Zinc/Erythromycin (topical) vs. Erythromycin (topical)

	There were two trials, single-site Trial 28271 and multi-country Trial 147,272 of patients with mostly moderate acne. Neither trial had methodologic limitations, although Trial 28 did not

specify the concentration of the erythromycin product. 

	Lesion counts in both treatment arms were statistically significantly reduced for non-

inflammatory and inflammatory lesions in both trials. The combination appears to have had an

effect on nodules that erythromycin alone did not in Trial 147, but the actual number of nodules

was small and no between-arm P-values were reported. The combination was reported to have

been better for comedones, for inflammatory lesions, and for overall severity assessment,

reaching statistical significance in the larger, but not the smaller, trial. Mild side effects appeared

about twice as often in the combination group, but numbers are too small for valid P-value

calculations. 

	There were two withdrawals from each arm due to local side effects.

N.08.03   –	Zinc Acetate/Erythromycin (topical) vs. Clindamycin  Phosphate (topical) 

	There was one large trial, Trial 300.273 Both treatments were effective on their own (although the authors simply state “significant,” without specifying a significance level). The differences

were in favor of erythromycin/zinc for changes in comedo, inflammatory lesions, and overall

severity. One patient from the erythromycin/zinc arm withdrew due to burning/redness.

N.08.04   –	Zinc Erythromycin (topical)/Placebo (oral) vs. Tetracycline (oral)/ Placebo (topical)

	There was one study, Trial 108,269 a medium four-arm trial of males 18-26 years old with comedonal acne.  The two treatments were comparable in percent change in papules and in

general severity.  No data on side effects were reported. (See N.08.01 for further information on

this trial.)

Psychological Outcomes 

	During review, two trials provided data for outcomes classified as psychological, beyond assessment of patient preference or satisfaction.  Trial 316,136 in comparison E.05.04, compared topical azelaic acid/glycolic acid versus topical tretinoin. Subjects rated the effect of each

treatment on a 6-point scale for the following factors: perceived attractiveness, self-confidence,

comfort in social situations, satisfaction with their appearance, ease in a physical relationship,

embarrassment, and degree to which acne negatively affected performance in work or at school.

There were no differences detected between the treatments for these outcomes. Trial 40,82  in comparison H.08.045, assessed cosmetic acceptability in patients treated with tetracycline orally

alone or in combination with topical tetracycline; acceptability was equivalent. No trials reported

outcomes related to longer-term psychological morbidities of acne or its treatment.

Compliance

	Although 43 trials provided some data on treatment compliance, only 12 trials (Trial 1,155 Trial 30,77 Trial 69,178 Trial 110,257 Trial 121,105 Trial 122,105 Trial 123,105 Trial 162,149 Trial 189,242 Trial 247,165 Trial 280,231 and Trial 338111) reported that they monitored compliance and provided explicit data regarding patients’ compliance. The detailed results are scattered across

treatments and serve only as anecdotal data.

Table 13. Summary of evidence for effectiveness

Comparison index	N	Severity	Target	Relative efficacy	Comparator	Evidence strength	Comments

A.01.01	114	Mild	Acidic syndet bar (topical)		Soap (topical)	C	

A.01.015	50	mod/sev	Aluminum oxide (topical)		Cleansers (topical)	C	

A.01.02		Mild/sev	Triclosan (topical)		Hexachlorophene  (topical)	C	

A.01.04	30	Mild	Povidone-iodine (topical)		Vehicle (topical)	C	

A.01.05	30	Mod	Silicic acid (topical)		Vehicle (topical)	C	

A.01.06		Mild/mod	Soybean liposome/glycolic acid

(topical)		Soybean liposome (topical)	C	

B.01.01	132		Azelaic acid (topical)	>	Vehicle (topical)	B	

B.01.02	309		Azelaic acid (topical)	=	Benzoyl peroxide (topical)	B	

B.01.03			Tretinoin (topical)	=	Azelaic acid (topical)	B	

B.01.04			Tetracycline (oral)		Clindamycin (oral)	C	

B.02.01			Tretinoin (topical)	=	Azelaic acid (topical)	B	

B.03.01	144	Mild/mod	Salicylic acid (topical)	>	Placebo (topical)	B	

B.03.02		Mild	Benzoyl peroxide (topical)		Salicylic acid (topical)	C	

B.04.01			Benzoyl peroxide (topical)	=	Sulfur/resorcinol (topical)	B	

B.04.02			Vitamin A (topical)	<	Keratolytics (topical)	B	"Keratolytics" includes

benzoyl peroxide.  From

E.06.02.

B.05.01	72	Mod	Polythionate/quaternary ammonia

complex of polythionate (topical)		Polythionate (topical)	C	

B.05.02	59	Mod	Sulfurated lime (topical)		Vehicle (topical)	C	

B.06.01	51	Mild/sev	Komed (sulfur/salicylic

acid/resorcinol) (topical)		Placebo (topical)	C	

B.06.02	51	Mild/sev	Komed (sulfur/salicylic

acid/resorcinol) (topical)		Proprietary formula

(sulfur/salicylic acid/resorcinol)	C	

B.07.01	25	Mild/mod	Aluminum chloride (topical)		Vehicle (topical)	C	

B.07.02	

776		Aluminum chlorhydroxide/sulfur

(topical)	>	Vehicle (topical)	A	

B.07.03	

		Methylprednisolone/neomycin

(topical)	<	Aluminum chlorhydroxide/sulfur

(topical)	C	

B.07.04	150	Mod/sev	Gluconolactone (topical)	>	Vehicle (topical)	B	inflammatory

B.07.05		Mod/sev	Benzoyl peroxide (topical)	<	Gluconolactone (topical)	B	

B.07.06	40	Mild/mod	Glycolic acid/soybean liposome

(topical)		Soybean liposome (topical)	C	

B.07.07		Mod	Clindamycin (topical)		Nicotinamide (topical)	C	

C.01.01	716	Mild/mod	Clindamycin (topical)	>	Vehicle (topical)	A	Clindamycin phosphate

and hydrochoride results

combined

C.01.02	76	Mod	Clindamycin (topical)		Nicotinamide (topical)	C	

C.01.03	753	Mild/sev	Clindamycin (topical)		Clindamycin (topical)	C	Phosphate vs

hydrochoride; lotion vs

gel vs solution

C.01.04	599	Mild/sev	Clindamycin (topical)	=	Erythromycin (topical)	B	

C.01.05	144	Mild/mod	Clindamycin (topical)	>	Tetracycline (topical)	B	

C.01.06	532	Mod	Clindamycin phosphate (topical)	=	Benzoyl peroxide (topical)	B	

C.01.07	

393		Clindamycin (topical)	<	Clindamycine/benzoyl peroxide

(topical)	B	

C.01.08		Mild/mod	Erythromycin/benzoyl peroxide

(topical)	<	Clindamycin phosphate (topical)	B	

C.01.09			Zinc/erythromycin (topical)	<	Clindamycin phosphate (topical)	B	

C.02.01		Mod	Clindamycin/benzoyl peroxide

(topical)	>	Vehicle (topical)	B	

C.02.02			Clindamycin (topical)	>	Clindamycine/benzoyl peroxide

(topical)	B	

C.02.03	472	Mod	Clindamycin/benzoyl peroxide

(topical)	>	Benzoyl peroxide (topical)	B	

C.03.01	1062	Mild/mod	Erythromycin (topical)	>	Vehicle (topical)	A	Especially inflammatory

C.03.02		Mild/sev	Clindamycin (topical)	=	Erythromycin (topical)	B	

C.03.025	94	mi/mod/sev	Erythromycin (topical)		Benzoyl peroxide (topical)	C	

C.03.03		Mod	Zinc/erythromycin (topical)	<	Erythromycin (topical)	B	

C.04.01	135		Fusiden (topical)	=	Vehicle (topical)	B	

C.04.02		Mild/mod	Doxycycline (oral)	=	Fusidic acid cream (topical)	B	

C.04.03		Mod/sev	Tetracycline/novobiocin (oral)	<	Placebo (oral)	B	

C.05.005	351	mod/sev	Meclocycline (topical)	>	Vehicle (topical)	B	Inflammatory

C.05.01	102	Mod	Meclocycline (topical)	<	Benzoyl peroxide (topical)	B	Comedones

C.05.02			Tetracycline (oral)	=	Azelaic acid  (topical)	B	

C.05.02		Mild/mod	Tetracycline (oral)	=	Meclocycline sulfosalicylate 

(topical)	B	

C.06.01	96		Metronidazole (topical)		Placebo (topical)	C	

C.07.01	

79		Neomycin (topical)		Keratolytics/anti-inflammatory

(topical)	C	

C.08.01	284	Mild/mod	Tetracycline (topical)	=	Vehicle (topical)	A	

C.08.02		Mild/mod	Clindamycin (topical)	<	Tetracycline (topical)	B	

C.08.03	69	Mod	Tetracycline (topical)	=	Benzoyl peroxide (topical)	B	

C.08.04			Tetracycline (oral)/povidone-iodine		Tetracycline (oral)	C	

C.08.05		Mod	Oxytetracycline (oral)		Tetracycline (topical) (oral)	C	

C.08.05			Oxytetracycline (oral)		Cotrimoxazole (oral)	C	

C.09.01	72	Mild/mod	Triclosan (topical)		Vehicle (topical)	C	

C.09.02	34	Mild/sev	Triclosan (topical)		Hexachlorophene  (topical)	C	

C.09.03	72	Mild/mod	Triclosan/propylene phenoxetol

(topical)		Vehicle (topical)	C	

D.01.01	1032		Benzoyl peroxide (topical)	>	Vehicle (topical)	A	

D.01.02			Azelaic acid (topical)	=	Benzoyl peroxide (topical)	B	

D.01.03	150	Mod/sev	Benzoyl peroxide (topical)	>	Gluconolactone (topical)	B	

D.01.04	30	Mild	Benzoyl peroxide (topical)		Salicylic acid (topical)	C	

D.01.05	189		Benzoyl peroxide (topical)	=	Sulfur/resorcinol (topical)	B	

D.01.06		Mod	Clindamycin phosphate (topical)	=	Benzoyl peroxide (topical)	B	

D.01.07		Mod	Meclocycline (topical)	>	Benzoyl peroxide (topical)	B	Comedones.  From

C.05.01.

D.01.08		Mod	Tetracycline (topical)	=	Benzoyl peroxide (topical)	B	

D.01.09	796	Mild/mod	Benzoyl peroxide (topical)	=	Benzoyl peroxide (topical)	A	

D.01.10	39	Mod	Benzoyl peroxide (topical)		Benzoyl peroxide/urea (topical)	C	

D.01.11		Mod	Meclocycline/benzoyl peroxide

(topical)	>	Benzoyl peroxide (topical)	B	Comedones.  From

D.06.01.

D.01.12		Mod/sev	Metronidazole/benzoyl peroxide

(topical)		Benzoyl peroxide (topical)	C	

D.01.13		Mod	Tretinoin (topical)	<	Benzoyl peroxide (topical)	B	

D.01.14			Vitamin A (topical)	<	Keratolytics (topical)	B	"Keratolytics" includes

benzoyl peroxide.  From

E.06.02.

D.01.15		Mod	Oxytetracycline (oral)		Benzoyl peroxide (topical)	C	

D.01.16		Mild/mod	Isotretinoin (topical)	<	Benzoyl peroxide (topical)	B	

D.01.17		Mod/sev	Miconazole/benzoyl peroxide

(topical)	<	Benzoyl peroxide (topical)	B	

D.01.18		Mod	Chloramphenicol/

hydrocortisone/sulfur		Benzoyl peroxide (topical)	C	

D.01.19		Mild/mod	Isolutrol (topical)		Benzoyl peroxide (topical)	C	

D.02.01		Mild/mod	Chloramphenicol/

hydrocortisone/sulfur		Chloramphenicol/sulfur (topical)	C	

D.03.01	92	Mild/mod	Benzoyl peroxide/glycolic acid/zinc

sulfur (topical)		Placebo (topical)	C	

D.03.02	161	Mild/mod	Benzoyl peroxide/

chlorhydroxyquinolone/

hydrocortisone (topical)		Benzoyl

peroxide/hydroxyquinolone

(topical)	C	

D.03.03	196	Mild/mod	Benzoyl

peroxide/chlorhydroxyquinolone/

hydrocortisone (topical)	=	Benzoyl

peroxide/chlorhydroxyquinolone

(topical)	B	

D.03.04	113	Mild/sev	Benzoyl peroxide/sulfur (topical)	>	Sulfur (topical)	B	

D.04.01	393	Mod	Clindamycin/benzoyl peroxide

(topical)	>	Vehicle (topical)	B	

D.04.02			Clindamycin (topical)	>	Clindamycine/benzoyl peroxide

(topical)	B	

D.04.03		Mod	Clindamycin/benzoyl peroxide

(topical)	<	Benzoyl peroxide (topical)	B	

D.05.01	92	Mild/mod	Erythromycin/benzoyl peroxide

(topical)		Placebo (topical)	C	medium

D.05.015	177	mod/sev	Erythromycin/benzoyl peroxide

(topical)		Erythromycin, benzoyl peroxide

(topical)	C	

D.05.02	205	Mild/mod	Erythromycin/benzoyl peroxide

(topical)	>	Clindamycin phosphate (topical)	B	

D.05.03	92	Mild	Erythromycin/benzoyl peroxide

(topical)		Benzoyl peroxide/glycolic

acid/zinc sulfur (topical)	C	medium

D.05.04	

72		Erythromycin/benzoyl peroxide

(topical)		Erythromycin/zinc (topical)	C	medium

D.05.05	

		Relaxation

training/erythromycin/benzoyl

peroxide (topical)		Erythromycin/benzoyl peroxide

(topical)	C	Similarly for Group

therapy control.  From

N.06.03.

D.05.06			Relaxation

training/erythromycin/benzoyl

peroxide (topical)		Erythromycin/benzoyl peroxide

(topical)	C	Similarly for Group

therapy control.  From

N.06.03.

D.06.01	102	Mod	Meclocycline/benzoyl peroxide

(topical)	<	Benzoyl peroxide (topical)	B	Comedones

D.07.01	43	Mod/sev	Metronidazole/benzoyl peroxide

(topical)		Vehicle (topical)	C	

D.07.02	60	Mod/sev	Metronidazole/benzoyl peroxide

(topical)		Benzoyl peroxide (topical)	C	

D.07.03		Mod/sev	Oxytetracycline (oral)		Benzoyl peroxide/metronidazole

(topical)	C	

D.08.01	177	Mod/sev	Miconazole/benzoyl peroxide

(topical)	>	Benzoyl peroxide (topical)	B	

D.08.02	

20		Miconazole/benzoyl peroxide

(topical)		Isoconazole/benzoyl peroxide

(topical)	C	

E.01.01	186	Mod/sev	Adapalene (0.03%) (topical)	<	Adapalene (0.1%) (topical)	B	

E.01.02	

1880		Adapalene (topical)	=	Tretinoin (topical)	A	Evidence B that

Adapalene more effective

for non-inflammatory

E.02.01	472	Mild/mod	Isotretinoin (topical)	>	Vehicle (topical)	A	

E.02.02	77	Mild/mod	Isotretinoin (topical)	>	Benzoyl peroxide (topical)	B	

E.02.03	82		Isotretinoin (0.05% topical)	=	Isotretinoin (0.1% topical)	B	

E.02.04	48		Isotretinoin (topical)		Tretinoin (topical)	C	

E.03.01	276		Motretinide (topical)		Vehicle (topical)	C	

E.03.02	60	Mod/sev	Motretinide (bid) (topical)	=	Motretinide (qd) (topical)	B	

E.03.03	354		Motretinide (topical)	=	Tretinoin (topical)	A	

E.04.01	

29		Retinyl beta-glucuronide (topical)		Vehicle (topical)	C	

E.04.02	

15		Retinyl beta-glucuronide (topical)		Tretinoin (topical)	C	

E.05.01	1248	Mild/mod	Tretinoin (topical)	>	Vehicle (topical)	A	Evidence type A for

non-inflammatory; Type B

for inflammatory.

E.05.015	

60		Tretinoin (topical)		Salicylate/resocinol/sulfur

(topical)	C	

E.05.02	494	Mod	Tretinoin (topical)	>	Benzoyl peroxide (topical)	B	

E.05.03			Motretinide (topical)	=	Tretinoin (topical)	A	

E.05.04	359		Tretinoin (topical)	=	Azelaic acid (topical)	B	

E.05.05			Isotretinoin (topical)		Tretinoin (topical)	C	

E.05.06			Retinyl beta-glucuronide (topical)		Tretinoin (topical)	C	

E.05.07	1010	Mild/sev	Tretinoin (topical)	=	Tretinoin (topical)	B	Compares different

strengths.

E.05.08	

68		Tretinoin (topical)		Methylprednisolone/neomycin

(topical)	C	

E.05.09	56	Mod	Tretinoin (topical)	=	Chloramphenical/hydrocortisone

(topical)	B	

E.06.01	147	Mild/mod	Vitamin A (topical)	>	Vehicle (topical)	B	Papules

E.06.02	

189		Vitamin A (topical)	>	Keratolytics (topical)	B	"Keratolytics" includes

benzoyl peroxide

E.06.03	238		Vitamin A (topical)	=	Oxytetracycline (oral)	B	

G.01.01	

80		Tretinoin/erythromycin (topical)		Vehicle (topical)	C	Other comparators as

well.

G.02.01	475	Mod/sev	Tretinoin/clindamycin (topical)		Clindamycin (topical)	B	Non-inflammatory

G.02.02	358	mod/sev	Tretinoin/clindamycin (topical)	>	Tretinoin (topical)	B	Inflammatory

G.02.03		mod/sev	Tretinoin/clindamycin (topical)		Tetracycline (topical)	C	

H.01.01	98	Mod	Clindamycin (oral)		Vehicle (oral)	C	

H.01.02	95		Clindamycin (oral)	=	Tetracycline (oral)	B	

H.02.01	401		Demethylchlortetracycline (oral)	=	Vehicle (oral)	B	

H.02.02	66		Demethylchlortetracycline (oral)		Phenethicillin (oral)	C	

H.02.03	250		Demethylchlortetracycline (oral)		Tetracycline (oral)	C	

H.03.01	62	Mild	Doxycycline (oral)	>	Placebo (oral)	B	More effective for

inflammatory. Equally

effective in

non-inflammatory.'

H.03.02	110	Mild/mod	Doxycycline (oral)	=	Fusidic acid cream (topical)	B	

H.03.03	56	Mod	Doxycycline (oral)		Erythromycin stearate (oral)	C	

H.03.04	140		Doxycycline (oral)		Minocycline (oral)	C	

H.04.01		Mod	Doxycycline (oral)		Erythromycin stearate (oral)	C	

H.04.02	40		Erythromycin base oral)		Erythromycin stearate (oral)	C	

H.04.03	278		Erythromycin (oral)	=	Tetracycline (oral)	B	

H.04.04	91	Mod/sev	Erythromycin (oral)		Triacetyl-oleandomycin (oral)	C	

H.04.05	

30		Roxithromycin (150 mg) (oral)		Roxithromycin (300 mg) (oral)	C	

H.04.06	142		Oleandomycin (oral)	=	Triacetyl-oleandomycin (oral)	B	

H.05.01	

43		Minocycline (oral)	>	Placebo (oral)	B	Inflammatory (P values

not given).

H.05.02	

144	Mod/sev	Minocycline (oral)	=	Clindamycin phosphate (topical)	B	

H.05.03			Doxycycline (oral)		Minocycline (oral)	C	

H.05.04	266	Mod/sev	Minocycline (oral)	=	Tetracycline (oral)	B	

H.06.01	76	Mod/sev	Oxytetracycline (oral)	>	Placebo (oral)	B	

H.06.02	69	Mod	Oxytetracycline (oral)		Benzoyl peroxide (topical)	C	

H.06.03	52	Mod/sev	Oxytetracycline (oral)		Benzoyl peroxide/metronidazole

(topical)	C	

H.06.04			Vitamin A (topical)	=	Oxytetracycline (oral)	B	

H.06.05	69	Mod	Oxytetracycline (oral)		Tetracycline (topical) (oral)	C	

H.06.05	69		Oxytetracycline (oral)		Cotrimoxazole (oral)	C	

H.06.06	16	Mild/sev	Oxytetracycline (oral)		Cotrimoxazole (oral)	C	

H.06.07	45		Oxytetracycline (oral)		Trimethoprim (oral)	C	

H.07.01	82		Cotrimoxazole (oral)	>	Placebo (oral)	B	

H.07.02	134	Sev	Sulfadimethoxine (oral)	>	Placebo (oral)	B	

H.08.01	945		Tetracycline (oral)	>	Vehicle (oral)	A	

H.08.02	506		Tetracycline (oral)	=	Clindamycin (topical)	B	

H.08.03	54	Mild/mod	Tetracycline (oral)	=	Erythromycin  (topical)	B	

H.08.04	284	Mild/mod	Tetracycline (oral)		Tetracycline (topical)	B	

H.08.045	

85		Tetracycline (oral)/Tetracycline

(topical)		Tetracycline (oral)	C	

H.08.05	639		Tetracycline (oral)	=	Azelaic acid  (topical)	B	

H.08.05	639	mod/sev	Tetracycline/sodium novobiocin (oral)		Placebo (oral)	C	

H.08.06	60	Mild/mod	Tetracycline (oral)	=	Meclocycline sulfosalicylate 

(topical)	B	

H.08.07			Clindamycin (oral)	=	Tetracycline (oral)	B	

H.08.08	

106		Tetracycline (oral)	=	Tetracycline (oral)	B	See text for treatment

details.

H.08.085	42	Mod/sev	Tetracycline/sodium novobiocin (oral)		Inert (oral)	C	

H.08.09		Sev	Isotretinoin (oral)		Tetracycline hydrochloride (oral)	C	

H.08.11		Sev	Gugulipid (oral)		Tetracycline (oral)	C	

H.08.12			Ocimum basilicum  (topical)		Tetracycline (oral)	C	

H.08.13		Mod/sev	Zinc sulfate/citrate complex (oral)	=	Tetracycline (oral)	B	

H.08.14	

30		Tetracycline (oral)/povidone-iodine		Tetracycline (oral)	C	

H.09.01	46		Dapsone (oral)		Placebo (oral)	C	

H.09.02	66		Phenethicillin (oral)		Placebo (oral)	C	

H.09.03			Demethylchlortetracycline (oral)		Phenethicillin (oral)	C	

H.09.04	70		Sodium fusidate (oral)		Sodium fusidate (topical)	C	

H.09.05	91	Mod/sev	Tetracycline/novobiocin (oral)	>	Placebo (oral)	B	

I.01.01	

211		Cotrimoxazole (oral)/sulfur/resorcinol

(topical)		Cotrimoxazole (oral)	C	

I.01.02	

211		Cotrimoxazole (oral)/sulfur/resorcinol

(topical)		Cotrimoxazole (oral)/tretinoin	C	

I.02.01	

122		Tetracycline (oral)/sulfur/salicylic

acid/polyethylene scrub	=	Tretinoin/benzoyl peroxide/water

avoidance (topical)	B	

J.01.01	

211		Cotrimoxazole (oral)/Tretinoin

(topical)		Cotrimoxazole (oral)	C	

J.01.02	

238		Oxytetracycline (oral)/vitamin A

(topical)	=	Oxytetracycline (oral)	A	

J.01.03	

122		Tetracycline (oral)/tretinoin/emollient 

(topical)	>	Tetracycline (oral)/sulfur/salicylic

acid/polyethylene scrub (topical)	B	Tretinoin/benzoyl

peroxide equally effective

(Type B) as

tetracyucline/tretinoin.

K.01.01			Isotretinoin (oral)		Altretinoin (oral)	C	

K.02.01	33	Sev	Isotretinoin (oral)		Placebo (oral)	C	

K.02.02	40	Sev	Isotretinoin (oral)		Dapsone (oral)	C	

K.02.03	30	Sev	Isotretinoin (oral)		Tetracycline hydrochloride (oral)	C	

K.02.04	26		Isotretinoin (oral)		Altretinoin (oral)	C	

K.02.05	56	Sev	Isotretinoin (oral)		Etretinate (oral)	C	medium

K.02.06	378	Sev	Isotretinoin (oral)	>	Isotretinoin (oral)	B	Some greater efficacy

with higher doses

K.03.01	80		Vitamin A (oral)		Placebo (oral)	C	

K.03.02	64	Mod/sev	Vitamin A (oral)		Zinc Sulfate (oral)	C	

M.01.01	45	Mild/mod	Cyproterone (topical)		Vehicle (topical)	C	

M.01.02	98	Mild/mod	Cyproterone/ethinyl estradiol (oral)		Minocycline hydrochloride (oral)	C	

M.01.03	

92		Cyproterone/ethinyl estradiol (oral)		Tetracycline/placebo (oral)	C	

M.01.04	45	Mild/mod	Cyproterone/ethinyl estradiol (0.035)

(oral)		Cyproterone (topical)	C	

M.01.05	302	Mod/sev	Cyproterone/ethinyl estradiol (0.05)

(oral)	=	Cyproterone/ethinyl estradiol

(0.035) (oral)	A	

M.01.06	90	Mod/sev	Cyproterone (2 mg)/ethinyl estradiol

(oral)		Cyproterone (0.05 mg)/ethinyl

estradiol (oral)	C	

M.01.07	

411		Cyproterone/ethinyl estradiol (0.035)

(oral)		Desogestrel/ethinyl estradiol

(oral)	C	

M.01.08	

133		Cyproterone/ethinyl estradiol (0.035)

(oral)	=	Levonorgestrel/ethinyl estradiol

(0.030) (oral)	B	

M.01.09	

90		Cyproterone (50)/ethinyl estradiol

(oral)		Norethisterone/placebo/ethinyl

estradiol (oral)	C	

M.02.01	24	Mild/mod	Desogestrel/ethinyl estradiol (oral)		Gestodene/ethinyl estradiol

(oral)	C	

M.02.02	87	Mild/mod	Desogestrel/ethinyl estradiol (oral)	>	Levonorgestrel/ethinyl estradiol

(oral)	B	

M.03.01	144	Mild/sev	Spironolactone (oral)	>	Placebo (oral)	B	

M.04.01	20		Delta-0.2%-chlormadione (oral)		Vehicle (oral)	C	

M.04.02	20		Delta-5%-chlormadione (oral)		Vehicle (oral)	C	

M.04.03	

20		Delta-0.2%-chlormadione (oral)		Delta-5%-chlormadione (oral)	C	

M.04.04	134		16-epiestriol-3-allyl ether (oral)	=	Placebo (oral)	B	

M.04.05	50		Epiestriol (oral)		Vehicle (oral)	C	

M.04.06	153	Mod	Inocoterone acetate (oral)	>	Vehicle (oral)	B	Inflammatory lesions.

Male patients

M.04.07			Cyproterone/ethinyl estradiol (0.035)

(oral)	=	Levonorgestrel/ethinyl estradiol

(0.030) (oral)	B	

M.04.08			Cyproterone (50)/ethinyl estradiol

(oral)		Norethisterone/placebo/ethinyl

estradiol (oral)	C	

M.04.09	507	Mild/mod	Norgestimate/ethinyl estradiol (oral)	>	Placebo (oral)	A	

M.04.10	60	Mild/mod	Quinestradol (oral)		Placebo (oral)	C	

M.04.11	40	Mild/sev	Serum gonadotrophin (oral)		Placebo (oral)	C	

N.01.01	82		Ayurvedic remedies (oral)		Placebo (oral)	C	

N.01.02	20	Sev	Gugulipid (oral)		Tetracycline (oral)	C	

N.01.03	70	Mild/mod	Isolutrol (topical)		Benzoyl peroxide (topical)	C	

N.01.04	51		Ocimum basilicum  (topical)		Tetracycline (oral)	C	

N.01.05	124	Mod	Tea tree oil (topical)	<	Benzoyl peroxide (topical)	B	Benzoyl peroxide better

for inflammatory, not for

non-inflammatory.

N.02.01	

11		Clobetasol (topical)		Vehicle (topical)	B	

N.02.02	

267		Hydrocortisone/neomycin/sulfur/

resorcinol (topical)		Components (topical)	C	

N.02.03	

188		Hydrocortisone (topical)		Hydrocortisone/sulfur (topical)	C	

N.02.04	

776		Methylprednisolone/neomycin

(topical)	>	Vehicle (topical)	B	

N.02.05	

182		Methylprednisolone/neomycin/sulfur

(topical)	>	Vehicle (topical)	B	

N.02.06	

824		Methylprednisolone/neomycin

(topical)	>	Aluminum chlorhydroxide/sulfur

(topical)	C	

N.02.07			Tretinoin (topical)		Methylprednisolone/neomycin

(topical)	C	

N.03.01	40		Gamma-globulin (parenteral)		Placebo (parenteral)	C	

N.03.02	39	Sev	Unfractionated dialyzable transfer

factor (topical)		Fractionated dialyzable transfer

factor (topical)	C	Also compared with

saline.

N.03.03	66		Staphylococcal toxoid (topical)		Vehicle (topical)	C	

N.04.01	32	Mild/mod	Chloramphenicol/hydrocortisone		Vehicle (topical)	C	

N.04.02	

120		Hydrocortisone/buttoxethyl

nicotinate/chloramphenicol	>	Vehicle (topical)	B	Comedones

N.04.03	50	Mild/mod	Chloramphenicol/hydrocortisone/

sulfur		Chloramphenicol/sulfur (topical)	C	

N.04.04	

37		Chloramphenicol/hydrocortisone/

sulfur		Hydrocortisone/sulfur (topical)	C	

N.04.05	48	Mod	Chloramphenicol/hydrocortisone/

sulfur		Benzoyl peroxide (topical)	C	

N.04.06		Mod	Tretinoin (topical)	=	Chloramphenical/hydrocortisone

(topical)	B	

N.05.01	250		Grenz rays		Sham rays	C	

N.05.02	

32		Comedone extraction 

(cheeks/forehead)		Untreated	C	

N.05.03	11		Fulguration		Tretinoin (topical)	C	

N.05.04	12		Fulguration		Electrocautery	C	

N.06.01	50	Mod/sev	Cimetidine [men] (oral)		Cimetidine [women] (oral)	C	

N.06.02	42	Mod	Contingent contract/benzoyl peroxide

(topical)		Benzoyl peroxide (topical)	C	Similarly for

non-contingent

contract/benzoyl peroxide

(topical)

N.06.03	

30		Relaxation

training/erythromycin/benzoyl

peroxide (topical)		Erythromycin/benzoyl peroxide

(topical)	C	Similarly for group

therapy control

N.06.04	92		Hydrochlorthiazide (oral)		Vehicle (oral)	C	

N.06.045	68	mild/mod	Ibuprofen/tetracycline (oral)		Placebo (oral)	C	

N.06.05	30	Mod	Tolbutamide (oral)		Vehicle (oral)	C	

N.07.01	30	Mild/mod	Zinc (topical)		Vehicle (topical)	C	

N.07.02	515		Zinc sulfate (oral)	>	Placebo (oral)	B	

N.07.03	88	Mod/sev	Zinc sulfate/citrate complex (oral)	=	Tetracycline (oral)	B	

N.08.01	244		Zinc/erythromycin (topical)		Vehicle (topical)	C	

N.08.02	167	Mod	Zinc/erythromycin (topical)	>	Erythromycin (topical)	B	

N.08.03	

103		Zinc/erythromycin (topical)	>	Clindamycin phosphate (topical)	B	

N.08.04	

149	

Mild	Zinc/erythromycin (topical)/placebo

(oral)		Tetracycline (oral)/placebo

(topical)		

Table 14. Summary of evidence for side effects

Comparison index	Target arm	Target side effects	Comparator arm	Comparator side effects	Relative efficacy	Assessment of evidence	Comments

A.01.01	Acidic syndet bar

(topical)	Itching/redness/scaling (4%:

2/57)	Soap	Itching/redness/scaling

(21%: 12/57)		B	

A.01.02	Hexachlorophene	Withdrew: erythema,

soreness (10%: 3/34)	Triclosan (topical)	Withdrew: erythema,

soreness (6%: 2/34)		C	From C.09.02.

A.01.03	Vehicle	**	Tretinoin (topical)	**	<	A	Local reactions. 

From E.05.01.

B.01.03	Azelaic acid	Erythema (15%: 27/177);

scaling (14%: 24/177)	Tretinoin (topical)	Erythema (27%:

48/181); scaling

(29%:52/181)	<	A	From E.05.04.

B.02.01	Azelaic acid	Erythema (15%: 27/177);

scaling (14%: 24/177)	Tretinoin (topical)	Erythema (27%:

48/181); scaling

(29%:52/181)	<	A	From E.05.04.

B.07.05	Gluconolactone	Local reactions (14%: 11/75)	Benzoyl peroxide

(topical)	Local reactions (29%:

22/75)	<	B	From D.01.03.

B.07.05	Gluconolactone

(topical)	Local reactions (25%: 11/45)	Vehicle	Local reactions  (11%:

5/45)	>	B	

B.07.06	Soybean liposome

(topical)	Withdrawals (0)	Glycolic

acid/soybean

liposome	Withdrawals (2/20)		C	

B.07.07	Nicotinanide	Local reactions (26%: 10/38)	Clindamycin (topical)	Local reactions (24%:

9/38)		C	From C.01.02.

C.01.01	Clindamycin (topical)	Severe: burning (0.2%:

1/539)	Vehicle	Severe: 0	=	B	

C.01.02	Clindamycin (topical)	Local reactions (24%: 9/38)	Nicotinanide	Local reactions (26%:

10/38)		C	

C.01.04	Clindamycin (topical)	Withdrew: 0/264	Erythromycin

(topical)	Withdrew (0.4%:

1/252)	=	A	

C.01.06	Clindamycin phosphate

(topical)	*	Benzoyl peroxide	*	=	B	

C.01.07	Clindamycin (topical)	Peeling (8%: 7/79)	Clindamycine/

benzoyl peroxide	Peeling (22%: 21/95)	<	B	

C.01.08	Clindamycin phosphate	Withdrew (0/100)	Erythromycin/

benzoyl peroxide

(topical)	Withdrew (3%: 3/99)	=	B	From D.05.02.

C.01.09	Clindamycin phosphate	Withdrew (0/52)	Zinc/erythromycin

(topical)	Withdrew (2%: 1/51)	=	B	From N.08.03.

C.02.01	Clindamycin/benzoyl

peroxide (topical)	Peeling (22%: 21/95)	Vehicle	Peeling (16%: 9/58)	>	B	

C.02.03	Clindamycin/benzoyl

peroxide (topical)	Peeling (22%: 21/95)	Benzoyl peroxide	Peeling (21%: 19/92)	=	B	

C.03.01	Erythromycin (topical)	Withdraw/severe (0.6%:

2/330)	Vehicle	Withdraw/severe

(0.3%: 1/330)	=	A	Across 4

studies

C.03.02	Erythromycin (topical)	Withdrew (0.4%: 1/252)	Clindamycin (topical)	Withdrew: 0/264	=	A	From C.01.04.

C.03.025	Erythromycin (topical)	Withdrew: dermatitis (2%:

1/48)	Benzoyl peroxide

(topical)	Withdrew: dermatitis

(2%:1/49)		C	

C.03.03	Erythromycin	Withdrew (2/61)	Zinc/erythromycin

(topical)	Withdrew (2/61)	=	B	From N.08.02.

C.08.01	Tetracycline (topical)	Skin discoloration (40%:

17/43); stinging (77%: 33/43)	Placebo	Skin discoloration

(10%: 4/42); stinging

(77%: 30/42)	>	B	Evidence

comparison for

skin

discoloration

C.09.02	Triclosan (topical)	Withdrew: erythema,

soreness (6%: 2/34)	Hexachlorophene	Withdrew: erythema,

soreness (10%: 3/34)		C	

D.01.01	Benzoyl peroxide

(topical)	Local reactions (29%: 22/75)	Vehicle	Local reactions (6%:

5/75)	>	B	

D.01.03	Benzoyl peroxide

(topical)	Local reactions (29%: 22/75)	Gluconolactone	Local reactions (14%:

11/75)	>	B	

D.01.06	Benzoyl peroxide	*	Clindamycin

phosphate (topical)	*	=	B	From C.01.06.

D.01.09	Benzoyl peroxide

(2.5%) (topical)	*	Benzoyl peroxide

(5%)	*		C	Mix of mild and

moderates side

effects

D.01.13	Benzoyl peroxide

(alcohol)	Local reactions (16%:

22/137)	Tretinoin (topical)	Local reactions (13%:

13/98)	=	B	Benzoyl

peroxide with

acetone had

apparently

fewer local

reactions.  From

E.05.02.

D.01.15	Benzoyl

peroxide/placebo (oral)	Severe: Facial reaction (4%:

1/24)	Oxytetracycline

(oral)/vehicle	Severe (0/22)		C	From H.06.02.

D.01.16	Benzoyl peroxide	Erythema (38%: 10/26)	Isotretinoin (topical)	Erythema (0/25)		C	Other side

effects

recorded. From

E.02.02.

D.01.19	Benzoyl peroxide	*	Isolutrol (topical)	*		C	Local reactions.

Between-arm P-

values

significant.

From N.01.03.

D.03.02	Benzoyl peroxide/

hydroxyquinoline

+hydrocortisone	*	Benzoyl peroxide/

hydroxyquinoline	*		C	

D.04.01	Clindamycin/benzoyl

peroxide	Peeling (22%: 21/95)	Vehicle	Peeling (16%: 9/58)	>	B	

D.04.02	Clindamycine/benzoyl

peroxide	Peeling (22%: 21/95)	Clindamycin (topical)	Peeling (8%: 7/79)	>	B	From C.01.07.

D.04.03	Benzoyl peroxide	Peeling (21%: 19/92)	Clindamycin/

benzoyl peroxide

(topical)	Peeling (22%: 21/95)	=	B	From C.02.03.

D.05.01	Erythromycin/benzoyl

peroxide (topical)	Scaling/tightness (30%:

14/46)	Placebo	Scaling/tightness (7%:

3/46)		C	

D.05.02	Erythromycin/benzoyl

peroxide (topical)	Withdrew (3%: 3/99)	Clindamycin

phosphate	Withdrew (0/100)	=	B	

D.05.03	Erythromycin/benzoyl

peroxide (topical)	Scaling/tightness (44%:

14/32)	Zinc/erythromycin

(topical)	Scaling/tightness

(13%: 4/30)		C	

D.08.02	Miconazole/benzoyl

peroxide (topical)	Local reactions (38%: 6/16)	Isoconazole/benzoyl

peroxide	Local reactions (38%

6/16)		C	

E.01.01	Adapalene (0.03%)

(topical)	Severe erythema (0/24)	Adapalene (0.1%)	Severe erythema (4%:

1/24)		C	

E.01.02	Adapalene (topical)	*	Tretinoin	*	<	B	

E.02.01	Isotretinoin (0.05%)

(topical)	**	Vehicle	**	>	A	Erythema and

peeling scores

give significant

P-values

between arms

E.02.02	Isotretinoin (topical)	Erythema (0/25)	Benzoyl peroxide	Erythema (38%: 10/26)		C	Other side

effects

recorded.

E.02.04	Isotretinoin (topical)	Local reactions+E59 (89%:

93/104)	Tretinoin	Local reactions (62%:

61/98)	>	B	

E.03.01	Motretinide (topical)	*	Vehicle	*	=	B	

E.03.03	Motretinide (topical)	**	Tretinoin	**	>	A	Local reactions

E.05.01	Tretinoin (topical)	**	Vehicle	**	>	A	Local reactions.

E.05.02	Tretinoin (topical)	Local reactions (13%: 13/98)	Benzoyl peroxide

(alcohol)	Local reactions (16%:

22/137)	=	B	Benzoyl

peroxide with

acetone had

apparently

fewer local

reactions.

E.05.04	Tretinoin (topical)	Erythema (27%: 48/181);

scaling (29%:52/181)	Azelaic acid	Erythema (15%:

27/177); scaling (14%:

24/177)	>	A	

E.05.05	Tretinoin	Local reactions (62%: 61/98)	Isotretinoin (topical)	Local reactions+E59

(89%: 93/104)	<	B	From E.02.04.

E.05.07	Tretinoin (0.02% to

0.1%)	**	Tretinoin (lower

strengths)	**	>	B	Local reactions.

One large study

with significantly

different rates,

the other

without

statistical

significance.

E.06.01	Vitamin A (topical)	Erythema (94%: 47/50)	Vehicle	Erythema (0/25)	>	B	

G.02.01	Tretinoin/clindamycin

(topical)	*	Clindamycin (topical)	*	=	B	

H.01.01	Clindamycin (oral)	Withdrew:

pseudomembranous colitis

(2%: 1/42)	Vehicle	Withdrew: 0/39		C	

H.02.01	Demethylchlor-

tetracycline (oral)	Photosensitivity (64%:46/72)	Placebo	Photosensitivity (5%:

3/56)	>	B	

H.02.03	Demethylchlor-

tetracycline (oral)	*	Tetracycline	*	=	B	

H.03.04	Doxycycline/placebo

(oral)	Withdrawals:

headache/dyspepsia (5%:

2/39)	Minocycline/placebo	Withdrawals:

dyspepsia, nausea,

vertigo (5%: 3/29)		C	

H.04.01	Tetracycline	Withdrew: vaginal

candidiasis (2% 1/50), visual

disturbance 2% (1/50)	Minocycline (oral)	Withdrew: vaginal

candidiasis (2%: 1/50),

persistent headache

(2%: 1/50)	=	B	From H.03.03.

H.04.02	Erythromycin (base)

(oral)	Withdrew: gastrointestinal 

distress (20%: 4/20)	Erythromycin

(stearate)	Withdrew:

gastrointestinal 

distress (4%: 1/20)		C	

H.04.03	Erythromycin (oral)	Withdrew (7%: 7/100)	Tetracycline (oral)	Withdrew (2%: 2/100)	=	B	

H.05.01	Minocycline (oral)	Withdrew: vertigo (4%: 1/19),

urticaria (4%: 1/18)	Placebo	Withdrew 0/18		C	

H.05.03	Minocycline/placebo	Withdrawals: dyspepsia,

nausea, vertigo (5%: 3/29)	Doxycycline/placebo

(oral)	Withdrawals:

Headache/dyspepsia

(5%: 2/39)		C	From H.03.04.

H.05.04	Minocycline (oral)	Withdrew: Vaginal

candidiasis (2%: 1/50),

persistent headache (2%:

1/50), hives (1/52)	Tetracycline	Withdrew: Vaginal

candidiasis (2% 1/50),

visual disturbance 2%

(1/50)	=	B	

H.06.02	Oxytetracycline

(oral)/vehicle	Severe (0/22)	Benzoyl peroxide/

placebo (oral)	Severe: Facial reaction

(4%: 1/24)		C	

H.06.07	Oxytetracycline (oral)	Withdrew (0/8)	Trimethoprim	Withdrew (25%: 2/8)		C	

H.08.045	Tetracycline (oral)/

tetracycline (topical)	Nausea (22%: 9/41)	Tetracycline (oral)	Nausea (12%:5/41)		C	

H.08.09	Tetracycline	Cheilitis (20%: 5/15)	Isotretinoin (oral)	Cheilitis (100%:15/15)		C	Other side

effects

recorded. From

K.02.03.

H.09.01	Dapsone (oral)	Side effects (26%: 6/23)	Placebo	Side effects (13%:

3/23)		C	

I.01.01	Cotrimoxazole (oral)/

sulfur/resorcinol

(topical)	Withdrew: erythema (7%:

5/71); desquamation (13%:

9/71), erythema (37%: 26/71)	Cotrimoxazole/

tretinoin	Withdrew: erythema

(28%: 19/69);

desquamation (36%:

25/69), erythema

(75%: 52/69)	<	B	

J.01.02	Oxytetracycline

(oral)/vitamin A (topical)	Erythema or desquamation

(84%: 66/79)	Oxytetracycline

(oral)/vehicle

(topical)	Erythema or

desquamation (32%:

25/79)	>	B	

K.02.01	Isotretinoin (oral)	Arthralgia (6%: 1/16)	Placebo (oral)	Arthralgia (0/17)		C	

K.02.02	Isotretinoin (oral)	Cheilitis (85%:17/20);

withdrew (0/20)	Dapsone (oral)	Cheilitis (0/20);

withdrew:

hypersensitivity (4%:

1/20)		C	

K.02.03	Isotretinoin (oral)	Cheilitis (100%:15/15)	Tetracycline	Cheilitis (20%: 5/15)		C	Other side

effects recorded

K.02.06	Isotretinoin (0.1) (oral)	Cheilitis ( 84%:27/32); severe

symptoms (14%:3/22)	Isotretinoin (1.0)

(oral)	Cheilitis (96%:23/24);

severe symptoms

(46%:11/24)		C	Other side

effects

recorded, plus

data for 0.5

mg/kg dose

M.01.05	Cyproterone/ethinyl

estradiol (0.05 mg)

(oral)	Withdrew (6%: 8/141);

severe (6%: 7/141)	Cyproterone/ethinyl

estradiol (0.035 mg)

(oral)	Withdrew (4%: 6/134);

severe (12%: 20/134)	=	B	

M.02.02	Desogestrel/ethinyl

estradiol (oral)	Withdrew: worse acne (8%:

2/26)	Levonorgestrel/

ethinyl estradiol	Withdrew: worse acne 

(14%: 4/28)		C	

M.03.01	Spironolactone (oral)	Withdrew: severe nausea

(3%: 2/58); menstrual

irregularity (19%: 11/58)	Placebo	Withdrew: severe

nausea (0/58);

menstrual irregularity

(0%: 0/58)	>	B	Menstrual

irregularity

M.04.06	Inocoterone acetate

(oral)	Local reactions (41%: 32/78)	Vehicle	Local reaction (32%:

24/75)	=	B	

M.04.08	Norgestimate/ethinyl

estradiol (oral)	Withdrew (10% :13/126)	Placebo	Withdrew (4% : 5/129)	>	B	

N.01.03	Isolutrol (topical)	*	Benzoyl peroxide	*		C	Local reactions.

Between-arm P-

values

significant.

N.01.05	Tea tree oil (topical)	Local reactions (44%: 27/61)	Benzoyl peroxide	Local reactions (82%:

50/61)	<	B	

N.04.01	Chloramphenicol/

hydrocortisone	Withdrew (0/15)	Vehicle	Withdrew (33%: 5/15)		C	

N.05.04	Fulguration	Withdrew: hypopigmentation

(18%: 2/11), discomfort (9%:

1/11)	Tretinoin	Withdrew (0/11)		C	

N.06.045	Ibuprofen/tetracycline

(topical)	Withdrew: (6%: 1/17)	Placebo	Withdrew: (6%: 1/17)		C	Similarly for the

tetracycline-only

and the

ibuprofen-only

arms.

N.07.02	Zinc (oral)	Withdrew: gastrointestinal 

distress (8%: 10/137);

gastrointestinal  symptoms

(16%: 22/137)	Placebo (oral)	Withdrew (0/127);

gastrointestinal 

distress (6%: 6/98)	=	B	Comparison of

withdrawals.

Comparison is >

(Level B) for

gastrointestinal 

distress. Pooled

trials that

reported side

effects.

N.08.02	Zinc/erythromycin

(topical)	Withdrew (2/61)	Erythromycin	Withdrew (2/61)	=	B	

N.08.03	Zinc/erythromycin

(topical)	Withdrew (2%: 1/51)	Clindamycin

phosphate	Withdrew (0/52)	=	B