J Clin Aesthet Dermatol. 2025;18(1):20–23.
by Zizi Yu, MD; Kirsten Swenson, MS, MBA; and Emmy Graber, MD, MBA
Dr. Yu is with the Boston University Department of Dermatology in Boston, Massachusetts. Ms. Swenson and Dr. Graber are with the Dermatology Institute of Boston in Boston, Massachusetts. Dr. Graber is additionally with Northeastern University in Boston, Massachusetts.
FUNDING: No funding was provided for this article.
DISCLOSURES: Dr. Graber is a consultant/speaker for Digital Diagnostics, Almirall, Beiersdorf, Cutera, Galderma, La Roche Posay, Ortho Dermatologics, Sebacia, Verrica, and WebMD. Dr. Graber has been provided with research grants from Almirall, Sebacia, and Ortho Dermatologics. Dr. Graber receives royalties from Wolters Kluwer Health and is a shareholder in Digital Diagnostics and Cutera. The remaining authors have no conflicts of interest to disclose.
ABSTRACT: Background: Acne vulgaris (acne) is a common disorder with a complex, multi-faceted pathophysiology. To date, there has not been a single topical treatment that targets all aspects of acne pathophysiology (ie, increased sebum production, presence of Cutibacterium acnes, inflammation, and follicular hyperkeratinization). As such, topical treatments need to be utilized in combination to target all four of the major recognized pathophysiologic components in acne lesion formation.
Objective: This single-center prospective evaluation assessed the safety, tolerability, and efficacy of clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel used concurrently with clascoterone 1% cream for treatment of acne in an eight-week, open-label pilot evaluation.
Methods: Six subjects (N=6), aged 21 to 27, were enrolled and evaluated at Week 0, Week 2, Week 4, and Week 8 with respect to erythema, dryness, and inflammatory lesion count (ILC).
Results: ILC decreased from 23.50 +/- 8.17 at baseline to 9.50 +/- 7.53 at Week 8 from baseline to Week 12. Average subject-reported adherence rate was 93.81%, and the most commonly reported side effects were burning/stinging and erythema; all were rated as mild.
Conclusion: This pilot evaluation, albeit small and open-label, demonstrates promising results for the first studied combination of topical agents to target all four aspects of acne pathophysiology. Further large-scale studies are needed to further elucidate the additive efficacy and side effect profile when these two topical medications are used concomitantly.
Keywords: Acne, topical therapy, clindamycin, benzoyl peroxide, adapalene
Introduction
Although a common disease, acne has a complex pathophysiology comprised of increased sebum production, presence of Cutibacterium acnes, inflammation, and follicular hyperkeratinization.1 Currently, oral isotretinoin is the only single medication that targets all four components of acne pathogenesis and has been found to be the most effective agent in treating acne.2 However, many patients are candidates and/or prefer topical therapy due to convenience and lower risk of systemic side effects. Currently, there is no single topical therapeutic agent that targets all four components of acne pathogenesis. A novel combination of clindamycin, benzoyl peroxide, and adapalene as a single gel was recently approved by the United States (US) Food and Drug Administration (FDA) to treat acne in patients over the age of 12 years. As the first FDA-approved, triple-combination topical acne product targeting all four pillars of acne pathogenesis, except for the cutaneous effects of androgens and sebum production, it has already shown superior results compared to reported therapeutic outcomes noted with multiple two-in-one combination topical treatments.3 In two, Phase III, randomized clinical trials, topical clascoterone cream 1% (Winlevi®, Sun Pharmaceuticals) for the treatment of acne demonstrated favorable efficacy and safety, with low adverse event rates.4 This prospective open-label pilot evaluation assessed the efficacy, safety, and tolerability of clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) (CABTREO®, Ortho Dermatologics) 3.1% gel used in combination with clascoterone 1% cream for the treatment of acne, the first described pilot evaluation using topical treatments in combination to target all four recognized pathways that are operative in acne pathogenesis.
Methods
This was a single-center, prospective, pilot evaluation to evaluate the efficacy, safety, and tolerability of clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel used concurrently with clascoterone 1% cream for the treatment of acne in an eight-week, open-label pilot evaluation. Institutional Review Board (IRB) approval was granted. All subjects signed a consent to participate in the pilot evaluation which included a photo consent for the use of any photographs taken throughout.
Subjects with a clinical diagnosis of acne, made by a board-certified dermatologist, who met all inclusion, and no exclusion criteria were enrolled. The pilot evaluation consisted of a minimum of four visits, which included a screening/baseline visit at Week 0, two-week follow-up (Visit 2), four-week follow-up (Visit 3), and eight-week follow-up (Visit 4). The subjects were given both study drugs for eight weeks at the baseline visit. “Study Drug A” refers to clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel and “Study Drug B” refers to clascoterone 1% cream. Due to the limited shelf life of 30 days after opening, Study Drug B was given to the subjects additionally at the Week 4 visit.5 Subjects were also provided with a gentle cleanser and moisturizer with sunscreen for use throughout the study period.
Inclusion criteria. Inclusion criteria consisted of the subject: (1) being between the age of 18 to 50 inclusive at screening, (2) having a facial Investigator Global Assessment (IGA) score of 2 (mild) or 3 (moderate), and (3) having a Fitzpatrick Skin Phototype of I to VI. Female participants of childbearing potential were required to be on a form of birth control at least 30 days prior to screening.
Exclusion criteria. Exclusion criteria included: (1) excessive facial hair, (2) more than five excoriated lesions, (3) isotretinoin use within 30 days of screening, (4) concomitant use of other topical prescription retinoids, (5) new hormone or hormone-regulating therapy 30 days prior to screening, (6) new antibiotic or change in antibiotics within 30 days of screening, (7) concomitant use of topical anti-acne medications (eg, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, minocycline or dapsone, unless already using these products at least 14 days prior and agree to continue for duration of pilot evaluation), (8) 1726nm laser treatment within 30 days of screening, and (9) any facial laser treatment within 14 days of screening. Subjects with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis were also excluded from the pilot evaluation, as Study Drug A prescribing information indicates that use is contraindicated in individuals with a history of these illnesses. Additionally, any female subject who was pregnant, nursing, or trying to become pregnant was excluded from the pilot evaluation.
Study protocol. Subjects were instructed to wash their face twice per day and pat dry with a soft towel prior to applying the study drug. Starting on Day 0, Study Drug B (approximately 0.5g or a fingertip unit) was to be applied to the entire face twice per day (morning and bedtime), and Study Drug A (approximately 0.2g or half of a fingertip unit) was to be applied to entire face once per day at bedtime followed by a second application of Study Drug B. A fingertip unit was defined as an amount of study drug applied from the distal skin crease to the tip of the index finger. Subjects were counseled to avoid contact with the mouth, eyes, and other mucous membranes and to wash their hands before and after application.
The investigator performed a facial skin exam to evaluate overall erythema, dryness, erosion, edema, inflammatory lesion count (ILC), and IGA score at every visit (Weeks 0, 2, 4, and 8). Overall diffuse erythema, erosion, edema, and dryness were graded on a scale of 0 to 3 (Tables 1 and 2). Standardized photography was performed at every visit and urine pregnancy tests were performed at every visit for female participants of childbearing potential.
A questionnaire was administered at the Week 2, 4, and 8 follow-up visits to evaluate skin tolerance of the medications. Subjects were asked about adverse events such as redness, dryness/flaking, itching, pain, and burning/stinging. Subjects were also asked to complete a daily diary recording doses applied or missed to track adherence. Subjects were asked to return the tubes of medication following completion and were compensated at Weeks 0, 2, 4, and 8.
The primary endpoints of the pilot evaluation were patient-reported tolerability of treatment and investigator-assessed clinical irritation from baseline to Week 8. The secondary endpoint was the mean change in ILC. A paired t-test was conducted to determine if there was a significant difference in lesion counts from baseline to Week 8. If the p-value was greater than 0.05, the null hypothesis would be accepted which states that the combination of Study Drugs A and B was not efficacious in the reduction of acne.
Results
Of the seven subjects enrolled in the pilot evaluation, six subjects (5 female, 1 male) completed and one subject was lost to follow-up following the Week 4 visit. This subject was not included in the statistical analysis. There was an overall statistically significant improvement in the ILC from baseline until Week 8 (p=0.01) and the improvement was statistically significant as early as Week 1 (p=0.03) (Table 2). The subjects ranged from 21 to 27 years of age (m=23.83) at time of screening. The Fitzpatrick Skin Types included Type I (n=2), Type II (n=2), Type IV (n=1) and Type V (n=1). No subject was using an additional concomitant topical or oral acne medication for the duration of the study.
The mean ILC decreased from 23.50 +/- 8.17 at baseline to 9.50 +/- 7.53 at Week 8 (Figure 1).
Diffuse erythema decreased from 0.33 +/- 0.52 at baseline to 0 at Week 8. Dryness remained stable at 0.17 +/- 0.41 at baseline and Week 8. Erosion decreased from 0.17 +/- 0.41 at baseline to 0 at Week 8. Edema remained the same at 0 at baseline and Week 8. One subject had an erythematous patch on preauricular area of right cheek at Week 4 which was possibly due to irritation from the study drugs. The subject also reported wearing over-the-ear headphones to sleep overnight which may have contributed to this event, documented as an adverse event. The patient discontinued use of the headphones and continued the study drugs with resolution of the dermatitis. No other adverse events reported through the duration of the pilot evaluation. Average subject-reported adherence rate throughout the eight weeks was 93.81 percent. Treatment adherence was assessed by the investigator or designated staff based on the diary card completion at each visit following the baseline visit. Adherent subjects were defined as those who completed 75 percent of the treatment applications and had not missed more than five consecutive days of dosing. The most reported drug-related side effects by the subject were burning/stinging and erythema. (Figures 2 and 3).
Discussion
This single-center, prospective, pilot evaluation demonstrated safety, tolerability, and efficacy of clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel once daily6 used concurrently with clascoterone 1% cream twice daily5 for the treatment of acne over an eight-week period. The most common side effects reported were mild burning/stinging and erythema after application of the study drugs, which did not significantly impact adherence, as adherence was favorable at over 90 percent. Further, this pilot evaluation demonstrated significant improvement in ILC with use of the two topical treatments. About 60-percent improvement was seen at eight weeks, and much of the improvement was rapid, occurring just one week after initiating treatment. Of note, IGA success, defined as at least a two-point improvement, is not reported in this pilot evaluation given that all patients enrolled started with an overall mild IGA score of 2, whereas many other acne studies enroll patients with IGA 3 or 4 at baseline and continue for 12 weeks in duration. Nevertheless, this pilot evaluation demonstrates promising results with respect to safety, tolerability, and efficacy of topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel and clascoterone 1% cream. The efficacy of these two study drugs in combination may be due to the ability to affect all four major components in acne pathogenesis, and this is the first pilot evaluation to use topical acne medications in combination to target all of these pathogenic factors. The results of this pilot evaluation are encouraging and further large-scale studies inclusive of a broad range of baseline acne severity and with longer follow-up periods are needed to elucidate the additive efficacy as well as the side effect profile of these two topical medications used in combination.
References
- Bellew S, Thiboutot D, Del Rosso JQ. Pathogenesis of acne vulgaris: what’s new, what’s interesting and what may be clinically relevant. J Drugs Dermatol. 2011;10(6):582–585.
- Huang CY, Chang IJ, Bolick N, et al. Comparative efficacy of pharmacological treatments for acne vulgaris: a network meta-analysis of 221 randomized controlled trials. Ann Fam Med. 2023;21(4):358–369.
- Stein Gold L, Baldwin H, Kircik LH, et al. Efficacy and safety of a fixed-dose clindamycin phosphate 1.2%, benzoyl peroxide 3.1%, and adapalene 0.15% gel for moderate-to-severe acne: a randomized phase ii study of the first triple-combination drug. Am J Clin Dermatol. 2022;23(1):93–104.
- Hebert A, Thiboutot D, Gold LS, et al. Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA Dermatol. 2020;156(6):621–630.
- Sun Pharmaceuticals.Winlevi (Clascoterone cream) for topical use: US prescribing information. 2020. https://www.winlevi-hcp.com/pdf/winlevi-prescribing-information.pdf
- Bausch Health Companies, Inc & Ortho Dermatologics. Cabtreo (clindamycin phosphate, adapalene, benzoyl peroxide gel) for topical use: US prescribing information. 2023. https://pi.bauschhealth.com/globalassets/BHC/PI/Cabtreo-PI.pdf