THERAPEUTICS FOR THE CLINICIAN Superiority of a Combined Contraceptive Containing Drospirenone to a Triphasic Preparation Containing Norgestimate in Acne Treatment Ian H. Thorneycroft, PhD, MD; Harald Gollnick, MD; Ilka Schellschmidt, MD This double-blind study compared the efficacy and investigators’ assessment of therapeutic effect on tolerability of a combined oral contraceptive contain- facial acne (ϩ3.6% in favor of EE/DRSP [95% CI, 0.8 ing 30 µg ethinyl estradiol and 3 mg drospirenone to 6.3; Pϭ.006]). The 2 preparations were compara- (EE/DRSP; Yasmin®) with a triphasic preparation ble as to their decreases in inflammatory lesion containing 35 µg EE and 0.180, 0.215, 0.250 mg count. Evaluation of the effect of treatment by sub- norgestimate (EE/NGM; Pramino®, also known as jects was consistent with that of the investigators. Ortho Tri-Cyclen®) in the treatment of acne vulgaris. Furthermore, both preparations increased the level of The combined presence of antiandrogenic and sex hormone–binding globulin (SHBG) and antimineralocorticoid activities of drospirenone is decreased the levels of androgens, changes typically unique to this novel progestin in that these character- associated with acne improvement. Both prepara- istics most closely resemble those of progesterone. tions were well tolerated. In conclusion, owing to the The study was designed to show that EE/DRSP was unique pharmacologic activities of drospirenone, the noninferior or superior to EE/NGM as to the relative combined oral contraceptive EE/DRSP provides an decrease from baseline to cycle 6 in percentage of effective treatment option in female patients with mild inflammatory and total lesion counts and the inves- to moderate acne. tigators’ assessment of acne improvement. Other Cutis. 2004;74:123-130. outcomes included subjects’ assessment of thera- peutic effect, sebum production, and hormone levels. lthough the causes of acne vulgaris are multifac- Female subjects were randomized to EE/DRSP torial, it is well accepted that androgenic hor- (nϭ568) or EE/NGM (nϭ586) for 6 treatment cycles, A mones play an important role in its pathogenesis.1 consisting of 21 consecutive days of hormone intake, Androgen overproduction or hypersensitivity of the followed by 7 hormone-free days. The preparation sebaceous glands to normal androgen levels can lead to containing EE/DRSP was superior to EE/NGM for increased sebum production and acne.1-3 As such, modu- reduction in total lesion count (Ϫ3.3% in favor of lation of androgen levels represents a valid treatment EE/DRSP [95% CI, Ϫ6.5 to Ϫ0.1; Pϭ.020]) and for option for acne in women. Evaluating effective therapies for acne is important, considering the potential adverse Accepted for publication May 13, 2004. psychosocial consequences of this skin disease. Dr. Thorneycroft is from the University of South Alabama, Mobile. Combined oral contraceptives are a highly effective Dr. Gollnick is from the University Clinic for Dermatology and treatment option for acne in women, particularly in those Venereology, Otto-von-Guericke-University, Magdeburg, Germany. 4-7 Dr. Schellschmidt is from Schering AG, Berlin, Germany. with symptoms of androgenization. The beneficial effects This study was supported by Schering AG, Berlin, Germany. of combined oral contraceptives on acne are partly due to Dr. Thorneycroft is an advisor for Berlex Laboratories and their ability to reduce androgen secretion by the ovaries Wyeth Pharmaceuticals. Dr. Schellschmidt owns shares and to increase the levels of sex hormone–binding globu- in and is an employee of Schering AG. Dr. Gollnick reports lin (SHBG).1 Moreover, some progestins, such as dros- no conflict of interest. Reprints: Ilka Schellschmidt, MD, Schering AG, Clinical pirenone (DRSP), cyproterone acetate, and dienogest, Development Gynecology & Andrology, 13342 Berlin, Germany have marked antiandrogenic activity, thereby partially (e-mail: [email protected]). counteracting the effects of endogenous androgens.8,9 VOLUME 74, AUGUST 2004 123 Therapeutics for the Clinician DRSP is a novel progestin and an analog of 17␣- face (inflammatory lesions). Before the baseline spironolactone that differs from all other available observation, washout periods had to be observed for progestins in that its pharmacologic properties (eg, oral contraceptives (Norplant® or Mirena® [3 cycles]); positive antimineralocorticoid and progestogenic systemic retinoids or Depo-Provera® (6 months); or activities and negative androgenic and glucocorticoid systemic antiacne agents, such as antibiotics (4 weeks), activities) most closely resemble those of proges- topical retinoids (4 weeks), and other topical treat- terone.8,10 Furthermore, DRSP has antiandrogenic ments (2 weeks). Other inclusion criteria included properties through direct actions at the androgen normal gynecologic examination and cervical smear receptor site, which, when combined with ethinyl within the last 6 months; negative pregnancy test; estradiol (EE) in an oral contraceptive, make it a 3 spontaneous withdrawal bleedings following deliv- suitable option in the treatment of acne and other ery, abortion, or lactation; and avoidance of comedo- skin-related conditions, in addition to other hyper- genic cosmetics or sunscreens, sex hormone androgenic disorders such as hirsutism.6,11 When preparations, and antiacne therapy. included in a combined oral contraceptive prepara- Subjects older than 30 years who smoked and tion, the antimineralocorticoid activity of DRSP also those who were pregnant or lactating were excluded may compensate for the increased fluid retention and from the study. Other exclusion criteria included acne associated weight gain attributed to estrogen. Further, comedonica or nodulocystic/conglobate acne; acne DRSP may help reduce follicular wall edema during with multiple large nodes, cysts, fistular comedones, the second half of the menstrual cycle, which is partly or abscessing fistular ducts; previous acne treatment responsible for the flare-up of inflammatory lesions at failure with (antiandrogenic) sex hormone prepara- this cycle phase.12 The combination of 30 ␮g EE and tions given for at least 3 months; and the need for 3 mg DRSP (Yasmin®) as a contraceptive is well other medication with known acne-inducing effects, 11,13,14 established, and its effect on acne and seborrhea such as lithium, vitamin B1, or corticoids. All subjects is comparable with a combined oral contraceptive were provided with a nonirritating skin care line (eg, containing 35 ␮g EE and 2 mg of the antiandrogenic cleansing gel, day cream) for use, as required. progestin cyproterone acetate.6 Treatment—Subjects were assigned randomly in This multicenter, randomized, double-blind clini- a 1:1 ratio, according to a computer-generated ran- cal trial was designed to compare the efficacy and tol- domization list, to receive EE/DRSP or a triphasic erability of EE/DRSP with a triphasic preparation oral contraceptive containing 35 ␮g EE and increas- containing 35 ␮g EE and norgestimate (NGM) in the ing doses of NGM (0.180 mg for days 1–7, 0.215 mg treatment of acne vulgaris. To date, this is the largest for days 8–14, and 0.250 mg for days 15–21 of each study designed to investigate the effect of oral contra- cycle)(EE/NGM; Pramino®). Subjects received ceptives on acne. their allocated treatment for 6 cycles; each cycle consisted of once-daily hormone treatment for Materials and Methods 21 consecutive days, followed by 7 hormone-free Study Design—This was a prospective, double-blind days. Treatment in cycle 1 began on the fifth day comparative study conducted from May 2000 to after the onset of menstruation, which was consid- September 2001 at 56 investigational centers in ered as day 1 of the treatment cycle. Russia (17), Germany (13), Ukraine (12), Czech Clinical Assessments—Subjects were evaluated dur- Republic (9) and Netherlands (5). This study was ing 9 visits for the following: screening for eligibility, approved by the appropriate ethics committees or randomization and assessment of dermatologic baseline, institutional review boards of the participating study treatment assessment on day 18Ϯ3 of cycles 1 to 6 and centers and was conducted in accordance with the end of study or posttreatment (between days 8–15 after ethical principles of the Declaration of Helsinki last capsule), or on premature discontinuation. At (amended in 1996) and the International Conference baseline and at each of the 6 treatment visits, a derma- on Harmonisation (ICH) good clinical practice tologist counted acne lesions over the entire face guidelines. All participants gave written and (defined as area bounded by the ears, hairline, and informed consent before enrollment. lower margin of the mandibles). The therapeutic effect Patients—Otherwise healthy female subjects rang- of treatment on acne and seborrhea was categorized ret- ing in age from 15 to 40 years without contraindica- rospectively by the dermatologist and the subject (by tions for combined oral contraceptive use with mild memory recall), as excellent, good, or moderate to moderate acne vulgaris were recruited for this improvement (collectively referred to as “improved”), study. A subject was eligible if she had 6 to 100 come- and no improvement or aggravation (collectively dones (noninflammatory lesions), 10 to 50 papules or referred to as “not improved”) at the last treatment visit pustules together, and not more than 5 nodules on the in cycle 6 or in cases of premature discontinuation. 124 CUTIS® Therapeutics