Acne is one of the most common chronic skin conditions observed in women. Androgen overproduction can be a major contributory factor to acne pathogenesis and is associated with hyperkeratinization of the hair follicle and increased sebum production by the sebaceous glands.1,2 Based on this evidence, alteration of androgen levels represents a potential hormonal treatment for acne in women, most commonly with use of combined oral contraceptive pills (OCPs).2–4
Combined OCPs were introduced in the 1960s and have become one of the most popular reversible methods of preventing unwanted pregnancies. Ethinyl estradiol, found in most combined OCPs, induces the synthesis of sex hormone–binding globulin, but these favorable effects of ethinyl estradiol may be negated by the inclusion of androgenic progestins.5
Drospirenone is a novel progestin that is a spironolactone analogue. It differs from other progestins in that it displays a pharmacologic profile similar to that of natural progesterone with both antimineralcorticoid and antiandrogenic properties.3,4,6,7 In the United States, drospirenone is the only progestin available that has demonstrated antiandrogenic activity. Furthermore, 3 mg of drospirenone has the equivalent antimineralocorticoid activity to 25 mg of spironolactone.8
A combined OCP comprising 3 mg of drospirenone/20 micrograms of ethinyl estradiol in a 24 active pill/four inactive pill (24/4) regimen has recently been developed and is now marketed in the United States and several other countries. This low-estrogen-dose formulation is well tolerated, has a favorable bleeding profile, and is a highly effective form of contraception that also alleviates the emotional and physical symptoms associated with premenstrual dysphoric disorder.5,9–11 Moreover, the U.S. Food and Drug Administration (FDA) has recently approved this formulation for the treatment of moderate acne vulgaris in women who desire an oral contraceptive for birth control.
This study was undertaken to estimate the efficacy and safety of six treatment cycles with 3-mg drospirenone/20-microgram ethinyl estradiol combined OCP in a 24/4 regimen in women with moderate acne.
MATERIALS AND METHODS
A double-blind, randomized study was conducted at 28 centers in the United States to compare the safety and efficacy of 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP with placebo in female patients with moderate acne vulgaris. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines and was also approved by the Independent Investigational Review Board. Signed, informed consent forms were obtained from the participants before they were entered in the study.
Girls and women aged 14 to 45 years (inclusive) who had a minimum of 20 inflammatory (papules or pustules) and 20 noninflammatory (comedones) facial lesions and who were classified as grade 3, 4, or 5 on the Investigator Static Global Assessment scale were eligible to be enrolled into the study. The inclusion age was 14 to 30 years (inclusive) for heavy smokers (more than 10 cigarettes per day), 14 to 35 years for lighter smokers (less than 10 cigarettes a day), and 14 to 45 years for nonsmokers. Participants were required to have had a normal Pap test within the last 6 months and at least 1 menstruation during the last 3 months before screening. General patient data were collected, including medical, dermatologic, and medication histories. In addition, the following procedures and tests were performed: physical and gynecologic examinations, serum pregnancy test, vital sign measurements, and safety laboratory tests. The standard skin-care regimen for all participants included the use of a mild soap/facial cleanser and noncomedogenic moisturizer and cosmetics, if desired. To be included in the study, it was necessary that participants agreed not to use any prescribed or over-the-counter topical or systemic acne treatment.
The exclusion criteria were consistent with the usual contraindications for combined OCP use, including pregnancy (delivery or abortion) or lactation within 3 months of the start of the study and unwillingness to use a nonhormonal method of contraception during the study. All participants were instructed to use nonhormonal contraceptives with the choices of condoms, diaphragm with spermicide, or nonhormonal intrauterine device during the entire study. Sterilization (participant or partner) was also an acceptable contraceptive method.
Use of additional steroid hormones, heparin, coumarin, hydantoins, barbiturates, phenytoin, primidone, carbamazepin, rifampicin, griseofulvin, topiramate, felbamate, ritonavir and products containing St. John’s wort, spironolactone, and continuous use of antibiotics were not permitted throughout this study. Previous anti-acne or contraceptive treatments were withdrawn 2 weeks to 6 months before the acne lesion count. Participants with the following dermatological conditions were also excluded from the study: acne and atopy, comedonal acne or acne conglobata; sandpaper acne or acne with multiple large nodes; cysts, fistular comedones, or abscessing fistular ducts.
Participants eligible for enrollment were randomly assigned on a 1:1 ratio to either 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP or placebo according to their computer-generated randomization code, based on the order of their randomization visit. The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP active treatment group received 24 consecutive days of hormonally active tablets followed by 4 consecutive days of inactive tablets. Participants in the placebo group received inert but identical-appearing, color-matched tablets and took 1 tablet per day, for a total of 28 tablets. The entire treatment period was six cycles, with 28 tablets per cycle. Both the participants and the investigators were blinded as to the study arm to which each participant was assigned to.
Compliance was assessed by analyzing participant recordings in diary card of tablet intake along with the return of used, partially used, or unused treatment packs. Treatment compliance was calculated as 100 times the number of pills taken divided by the study duration.
Subjects were assessed at initial screening (visit 1) and random assignment (visit 2) and then at day 15±3 days of cycle 1 (visit 3), cycle 3 (visit 4), cycle 6 (visit 5), and finally at follow-up, 8–15 days after the last tablet was taken (visit 6). Acne lesion counts, Investigator Static Global Assessment, review of compliance, adverse events, concomitant medications, and vital sign measurements were assessed at treatment cycles 1, 3 and 6.
The primary efficacy variables for this study were percentage change from baseline in inflammatory (papules, pustules, and nodules) and noninflammatory (open and closed comedones) lesion counts and the percentage of participants classified as clear (score 0) or almost clear (score 1) on the Investigator Static Global Assessment scale. The six-point scale ranged from 0 (normal, clear skin) and 1 (almost clear) to 5, (numerous inflammatory and noninflammatory acne lesions).
Other efficacy assessments based on subgroup analyses for age (split into age groups of 14–22 years, 22–26 years, 27–30 years, 31–34 years and 35–45 years) and race (white, African American, Hispanic, Asian and other subgroups) were performed.
Safety was evaluated by clinical laboratory test results, adverse events, physical and gynecologic examinations, and vital sign measurements. The relationship of any adverse events to the study drug were defined as definite, probable, possible, unlikely, or none and were coded using the Hoechst Adverse Reaction Terminology System and serious adverse events (SAEs) were coded using Medical Dictionary for Drug Regulatory Activities.
The sample size was calculated by using data from two previously published studies,2,12 which compared the efficacy of a triphasic combined OCP (norgestimate-ethinyl estradiol) with placebo for the treatment of moderate acne. The average mean percent difference from baseline to cycle 6 in lesion counts for the intent-to-treat groups was 47.80% for active treatment and 30.26% for placebo (with a pooled standard deviation [SD] of 50.16%) for inflammatory lesions and 41.74% for active treatment and 27.52% for placebo (with a pooled SD of 39.02%) for total lesions. Based on these studies, a sample size of 250 women per group, assuming a dropout rate of 20%, would provide more than 90% power to detect differences of similar magnitudes in our study. For noninflammatory lesions, assuming a common SD of 55 (the pooled SD for noninflammatory lesions observed in these studies) and a 20% dropout rate, 90% power would be provided to detect a difference between treatment and placebo of 18.0 lesions. Assuming that 40% of participants in the active treatment group are classified as clear or almost clear on the Investigator Static Global Assessment scale and a 20% dropout rate, this sample size would provide more than 90% power to detect a difference of 16% or more between active treatment and placebo.
The safety analysis set consisted of all randomly assigned participants who were dispensed trial medication and were part of the intent-to-treat set. The inclusion criterion for the full analysis set was amended according to FDA requirements to change the indication from mild to moderate acne vulgaris (inclusion criterion of 10 to 100 comedones, 10 to 50 inflammatory lesions, and not more than 5 nodules) to moderate acne vulgaris. Participants who met the amended inclusion criterion of a minimum of 40 facial lesions in total, including 20 inflammatory and 20 noninflammatory lesions, were part of the amended full analyses set and were regarded as the primary analysis set.
For the primary efficacy variables, comparisons of the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and the placebo group were made at the endpoint with an analysis of covariance model, with percent change from baseline as the response, treatment and center as factors, and the baseline values as the covariate. For the lesion counts, the tested null hypothesis was that the mean percent change from baseline in the lesion count for the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group was equal to that for the placebo. Similarly, the null hypothesis tested for the Investigator Static Global Assessment scale was that the percent of participants classified as clear or almost clear for the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group was equal to that for the placebo group.
The first participant was enrolled on January 23, 2003, with final follow-up taking place on August 19, 2004. Of the 784 participants screened, 538 were randomly assigned and dispensed study medication. There were 431 participants in the amended full analysis set (218 in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and 213 in the placebo group) and included only participants with a minimum of 40 total lesions, including 20 inflammatory and 20 noninflammatory lesions. Baseline characteristics and flow through the study are presented in Table 1 and Figure 1.
The mean treatment compliance in the amended full analysis set for the 3-mg drospirenone/20-microgram ethinyl estradiol and placebo groups was 87.6% and 86.0%, respectively. There were 188 (86.2%) participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and 180 (84.5%) participants in the placebo group who were at least 80% compliant.
The amended full analysis set was used for the primary efficacy analysis. At baseline, the mean lesion count was comparable between the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and the placebo group (31.7 and 31.8 for inflammatory lesions, 43.9 and 43.9 for noninflammatory lesions and 75.7 and 75.7 for total lesions, respectively).
The percentage reduction from baseline to endpoint for total lesions is 46.3% for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6% for placebo group (P<.001).
By cycle 3, a greater percentage reduction in all lesion counts in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group compared with the placebo group was observed and maintained throughout the rest of the study duration, as presented in Figure 2. Moreover, the percentage reduction from baseline to cycle 3 was statistically significant (P<.05) in inflammatory and total lesion counts in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group compared with the placebo group.
There was a notable increase in the percentage of participants with an Investigator Static Global Assessment rating of clear or almost clear from baseline to endpoint, with this increase being greater in the active treatment group than in the placebo group. There was a significantly higher probability that participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group had an Investigator Static Global Assessment rating of clear or almost clear (proportion=21.1%) compared with the placebo group (proportion=8.9%). The resulting odds ratio was 3.131 (confidence interval 1.688–5.806; P=.001), as outlined in Figures 3 and 4.
The age groups assessed were 14–22 years, 23–26 years, 27–30 years, 31–34 years and 35–45 years. This subgroup analysis showed that, in all age groups, the mean percentage change from baseline to endpoint in inflammatory, noninflammatory, and total lesion count was greater in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP subgroups than in the respective placebo subgroups (Fig. 4). The percentage of participants rated as clear or almost clear on the Investigator Static Global Assessment scale at endpoint was higher in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group than in the respective placebo subgroups for all age groups, except the 23–26-years group. The largest difference between treatment groups was seen in the 14–22-years age group, which had the highest reduction in the mean percentage change from baseline to endpoint in inflammatory lesion count (P<.001) and the highest percentage of participants rated as clear or almost clear on the Investigator Static Global Assessment scale (P<.001) at endpoint in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group compared with the respective placebo group (Figure 4).
Subgroup analysis of race included whites, African Americans, Hispanics, Asians and other. Whites, African Americans, and Hispanics in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP subgroups all had greater reductions in mean percent change from baseline to endpoint in inflammatory, noninflammatory, and total lesion counts compared with respective placebo subgroups. The number of participants in the Asian and other subgroups was too small to make any conclusions.
There were 538 participants (270 participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and 268 in the placebo group) in the safety analysis set. Treatment related adverse events occurring in more than 2% of participants in either treatment groups are presented in Table 2. The proportion of participants who reported at least one adverse event in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group was 55.2% (149 participants) compared with 45.9% (123 participants) in the placebo group; overall the proportion of participants reporting at least one adverse event were similar among the two treatment groups. Overall, the majority of the treatment-emergent adverse events were rated by the investigator as mild or moderate in intensity in both the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group (51.5%) and the placebo group (39.6%).
One participant (0.4%) in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and five (1.9%) participants in the placebo group reported SAEs. The treatment-emergent SAEs were pneumonia in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and drug abuse, pelvic pain, convulsions, ectopic pregnancy, abdominal pain, and accidental injury in the placebo group and, all of which were unlikely to be or definitely not related to the study drug. There were 16 participants (5.9%) in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and 9 participants (3.4%) in the placebo group who prematurely discontinued the study due to an adverse event.
Two participants (0.8%) in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group and five participants (2.0%) in the placebo group reported at least one postbaseline serum potassium reading of 5.5m Eq/L or higher. However, none of these cases were regarded as clinically relevant by the investigators and none of these participants experienced any adverse events related to increased potassium levels. Overall, there was no indication of increased risk of hyperkalemia, and no thromboembolic adverse events were reported. There were no unexpected or unusual clinical laboratory findings, and the majority of participants had normal physical and gynecological examinations (including Pap test).
In the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP group, there were four (1.5%) ongoing pregnancies at the end of the study or at premature discontinuation; two participants became pregnant before study medication intake, and two participants became pregnant during treatment phase (one participant in cycle 1 and one participant in cycle 4) due to noncompliance. In the placebo group, there were eight (3.0%) ongoing pregnancies, one (0.4%) abortion, one (0.4%) ectopic pregnancy, and one (0.4%) participant categorized as other (lost to follow-up due to pregnancy).
Mean body weight slightly decreased over time during the treatment phase in the 3-mg drospirenone/20-microgram ethinyl estradiol combined OCP 24/4 group while the placebo group demonstrated a slight decrease in mean body weight at treatment cycle 1 followed by small increases for the remainder of the treatment phase. Weight change between the two treatment groups was not statistically significant.
In this multicenter, randomized, placebo-controlled trial, 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP was significantly more effective than placebo in the treatment of moderate acne vulgaris as determined by lesion counting and Investigator Static Global Assessment rating. In addition, it was well tolerated, and its safety profile was consistent with that of other low-dose combined OCPs.
This was one of two identically designed studies (Lucky AW, Koltun W, Thiboutot D, Niknian M, Sampson-Landers C, Korner P, Marr J. Efficacy and safety of 3 mg drospirenone/20 μg EE 24/4 in the treatment of acne vulgaris: lesion counts, subject self-assessment. CUTIS. In press)12 that were conducted to determine the efficacy and safety of 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP for the treatment of acne vulgaris. The consistency of the positive results among the two studies led to the recent FDA approval of this formulation for the treatment of moderate acne vulgaris in women who desire an oral contraceptive for birth control.
While all combined OCPs have an estrogen-induced effect on sex hormone–binding globulin, many progestins somewhat mitigate this effect with their androgenic properties. In contrast, drospirenone is the only progestin available in the United States that has demonstrated antiandrogenic properties. The combination of the 24/4 regimen plus the 30-hour half-life of drospirenone means that the dual mechanisms of antiandrogenic activity (sex hormone–binding globulin effect and antiandrogenic effect at the androgen receptor) are present throughout the cycle with the 3-mg drospirenone/20-mg ethinyl estradiol formulation. Moreover, the current study with the 3-mg drospirenone/20-mg ethinyl estradiol 24/4 regimen has shown a comparable reduction in total acne lesion counts demonstrated in previous studies with other non–drospirenone-containing combined OCPs.2,13 These anti-acne effects may be attributed to the fact that the 3 mg drospirenone/20 mg ethinyl estradiol 24/4 regimen comprises a progestin with anti-androgenic properties as well as a sex hormone–binding globulin-inducing estrogen component.
The placebo response observed was consistent with that found in combined OCP studies,2,12–15 which may be explained, in part, by increased motivation of study participants to skin care hygiene before acne assessments by the physicians or spontaneous resolution of the condition.
The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen combined OCP was well tolerated in this study, and its adverse event profile was consistent with that for other low-dose combined OCPs. In addition, as previously observed with other drospirenone-containing combined OCPs, the mean body weight slightly decreased over time during the treatment phase in the 3-mg drospirenone/20-microgram ethinyl estradiol combined OCP 24/4 group, compared with a slight increase observed in the placebo group.
Subjects treated with 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combined OCP regimen had a significantly greater percentage decrease in acne lesion counts than those treated with placebo, and these anti-acne effects were observed by cycle 3 of treatment. This new combined OCP formulation demonstrated a good safety and tolerability profile. Moreover, the incidence and types of adverse events reported in this study were comparable with those reported with other low-dose combined oral contraceptives.
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