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Daily treatment with adapalene gel 0.1% maintains initial improvement of acne vulgaris previously treated with oral lymecycline

European Journal of Dermatology. Volume 17, Number 1, 45-51, January-February 2007, Therapy

DOI : 10.1684/ejd.2007.0188

Summary

Author(s) : Mohsen Alirezai, Sheru A George, Ian Coutts, Diane I Roseeuw, Jean-Pierre Hachem, Nabil Kerrouche, Farzaneh Sidou, Pascale Soto , Service de dermatologie, Hôpital Saint Eloi, Montpellier, France, Department of Dermatology, Amersham Hospital, Amersham, UK, AZ-VUB Dermatologie, Brussels, Belgium, Galderma, Sophia Antipolis, France.

Summary : Topical retinoids are often recommended for preventing acne recurrence, but there are relatively few well-controlled maintenance studies published. The objective of the present study was to assess the maintenance effect of adapalene gel 0.1% relative to gel vehicle in subjects successfully treated in a previous 12-week adapalene-lymecycline 300 mg combination therapy study. This was a multicentre, investigator-blind, randomised, controlled study in 19 European centres. A total of 136 subjects with moderate to moderately-severe acne vulgaris who showed at least moderate improvement from baseline when treated with either adapalene plus lymecycline or lymecycline plus gel vehicle in a previous 12 week study were included. Subjects were randomised to receive adapalene gel 0.1% or vehicle once-daily for 12 weeks. Efficacy and safety criteria included maintenance rate, percent reduction in lesion counts (total, inflammatory, non inflammatory), global severity assessment, cutaneous tolerability, and adverse events. Adapalene provided better results relative to gel vehicle for all efficacy assessments. The maintenance rate for total lesions was 84.7% vs. 63.5% (P \= 0.0049) with adapalene and the vehicle, respectively. Adapalene was safe and well tolerated in this study. This study demonstrates a clinical benefit of continued treatment with adapalene gel 0.1% as a maintenance therapy for acne.

Keywords : Topical retinoids, acne, maintenance therapy, adapalene

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ARTICLE

Auteur(s) : Mohsen Alirezai¹, Sheru A George², Ian Coutts², Diane I Roseeuw³, Jean-Pierre Hachem³, Nabil Kerrouche⁴, Farzaneh Sidou⁴, Pascale Soto⁴

¹Service de dermatologie, Hôpital Saint Eloi, Montpellier, France
²Department of Dermatology, Amersham Hospital, Amersham, UK
³AZ-VUB Dermatologie, Brussels, Belgium
⁴Galderma, Sophia Antipolis, France

accepté le 23 Août 2006

Acne vulgaris is a common, chronic and recurrent disease. Management of the moderate to moderately severe forms often requires aggressive combination therapy to account for the multiple associated etiological factors and a long-term therapeutic strategy [1-5]. The recurring nature of acne suggests that many patients may benefit from continuing on a maintenance therapy [5]. Ideally, regular use of topical retinoids should help ensure visible acne lesions remain in remission [6].The goal of maintenance therapy should be to prevent acne recurrence by targeting the early stages of comedogenesis, thereby suppressing the development of subclinical microcomedones, the precursor of mature acne lesions [5, 6]. Topical retinoids are effective, generally well-tolerated comedolytic agents that can be applied to a broad epidermal surface and therefore make a rational choice for maintenance therapy. Furthermore, topical retinoids are well suited to prevent the formation of microcomedos, as they are the only acne medication that regulate the keratinisation process from within the duct [7]. Recently published guidelines recommend the use of topical retinoids with or without benzoyl peroxide for maintenance following initial combination treatment with an antimicrobial [5]. Despite support from leading guidelines and the variety of medications available for the treatment of acute acne, there are relatively few well-controlled studies providing evidence for long-term or maintenance therapy.Most of the available clinical evidence for successful maintenance therapy is with adapalene [8-10], a naphthoic acid derivative, receptor-selective retinoid with anti-inflammatory, comedolytic, and anticomedogenic properties [11-16]. The efficacy and safety of adapalene in the treatment of acne vulgaris have been extensively studied in numerous clinical trials [17, 18] either alone or in combination with antimicrobials and have consistently demonstrated a more favourable tolerability profile than other topical retinoids, including all tazarotene [19, 20] and tretinoin [20-23] formulations. For the treatment of inflammatory acne, the efficacy of a combination therapy of adapalene plus antibiotic therapy is significantly better and faster than therapy with antibiotic therapy alone (oral or topical) for the treatment of inflammatory acne [8, 9, 24-27]. Furthermore, several studies have shown clinical benefit of continued treatment with adapalene gel 0.1% as a maintenance therapy following the combination therapy with an antibiotic [8-10].The present study is intended to confirm these previous studies and provide further support for recommendations from the current guidelines. In an initial study, the efficacy and safety of adapalene was evaluated when used in combination with oral lymecycline by moderate to moderately severe acne subjects for 12-weeks [24]. Lymecycline, a semisynthetic tetracycline antibiotic, is a first-line antibiotic for acne with improved oral absorption, enhanced tissue penetration, and slower elimination relative to tetracycline [25]. Subjects were randomised to receive lymecycline 300 mg and either adapalene gel 0.1% or vehicle once-daily. At week 12, the combination of adapalene-lymecycline produced significantly larger reductions in total, inflammatory, and non-inflammatory lesions relative to lymecycline alone, similar to results from other adapalene-antimicrobial studies [8, 9, 26, 27].In the present study, the maintenance effect of adapalene gel 0.1% was evaluated relative to its gel vehicle in those subjects who showed at least moderate improvement from the previous adapalene-lymecycline combination therapy study. The results of this maintenance study are presented herein.

Methods

Study design and subjects

The efficacy and safety of adapalene gel 0.1% (Differin^® Gel 0.1%, Galderma International) as a maintenance therapy were compared to its gel vehicle in a randomised, multicentre, vehicle-controlled, investigator-blind, parallel group study conducted at 19 centres in Europe. Male and female acne subjects, 12 to 30 years of age, were enrolled if they showed at least moderate improvement (on the following 7-point scale of disease improvement: Worse; No change; Slight improvement: approximately 1-24% improvement; Moderate improvement: 25-49% improvement; Marked improvement: 50-74% improvement; Almost clear: 75-99% improvement; Clear: 100% improvement) from the starting point of a previous 12-week treatment with either adapalene plus lymecycline or gel vehicle plus lymecycline [24]. In this prior combination study, a total of 242 subjects, with a global severity grade ranging from 4 to 10 on the Leeds Revised Acne Grading System [28] and with at least 15 inflammatory facial lesions (no more than 3 nodules) and at least 20 non inflammatory facial lesions, were randomized to receive lymecycline 300 mg once-daily in the morning and either adapalene or gel vehicle once-daily in the evening for 12 weeks. Eligible subjects completing that study were re-randomised consecutively in a 1: 1 ratio to receive either adapalene gel 0.1% or adapalene gel vehicle once-daily in the evening for an additional 12 weeks as part of the current study. The randomisation schedule remained blinded from those involved in the clinical conduct of the study. The integrity of the blinding was ensured by packaging the topical medication in identical tubes and requiring a third party other than the investigator/evaluator to dispense the medication.

Exclusion criteria prohibited enrollment of subjects with acne requiring isotretinoin therapy or other dermatologic conditions necessitating interfering treatment. Women were excluded if they were pregnant, nursing, or planning a pregnancy, as were men with facial hair that would interfere with the assessments. Subjects were provided with a daily facial moisturizer to use as needed for the symptomatic relief of skin dryness or irritation.

Evaluations for this study occurred at baseline and at weeks 4, 8, and 12. The final visit from the previous 12-week combination study served as the baseline visit for this study. A urine pregnancy test was required at entry and at the final study visit for all females of childbearing potential. Subjects were free to withdraw from the study at any time and for any reason. Subjects not completing the entire study were to be fully evaluated when possible.

This study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and Good Clinical Practices (GCPs), ICH guidelines, and in compliance with local regulatory requirements. This study was reviewed and approved by Independent Ethics Committees. All subjects provided their written informed consent prior to entering the study.

Efficacy and safety variables

The main objective was to evaluate the maintenance success rate at the end of the maintenance study, defined as the percentage of subjects who maintained at least 50% of the improvement (in terms of percent reduction of lesions [total, inflammatory and non inflammatory]) from the previous 12-week combination therapy study (e.g., a subject entering the maintenance phase after having lost 60% lesions [from 80 to 32 lesions] was considered as a failure if the % reduction at the end of the maintenance study was inferior to 30% [56 lesions]. Other efficacy variables included median of percent reduction in lesion count (total, inflammatory and non inflammatory) from starting point of the previous combination study, and global severity of the disease by use of the Leeds Revised Acne Grading System [28].

Safety and tolerability were assessed through evaluations of local facial tolerability and adverse events. At each visit, the investigator rated erythema, scaling, dryness, and stinging/burning on a scale ranging from 0 (none) to 3 (severe). Mean scores at each post baseline visit and worst score (worst observation recorded for a subject during the post baseline period) were calculated. Adverse events were also evaluated at each visit.

Statistical analyses

In this study, the safety population was defined as all subjects randomised and treated at least once. The intent-to-treat (ITT) population included all randomised subjects who were dispensed study medication. To evaluate the effect of major deviations or of data exclusions, the ITT population was analysed using a worst case method to impute missing values. All subjects with missing data were considered failure subjects. Therefore, at week 12, for the maintenance rate variable, the “failure” value was attributed to missing data. To be consistent with maintenance rate, the median of percent reduction of failure subject population was attributed to missing data for the descriptive analyses of lesions.

Analyses for the maintenance rate were performed on the week 12 data for the ITT-worst case population. To evaluate the efficacy of the maintenance therapy between the two treatment arms, the success rate in terms of lesions (total, inflammatory and non inflammatory) were analysed by the Cochran-Mantel-Haenzsel (CMH) test controlling for previous treatment using ridit scores, at week 12. Global severity was analysed using the Cochran-Mantel-Haenzsel (CMH) test controlling for “analysis centre” and previous treatment. Percent reduction from starting point of the previous combination study in lesions counts was descriptively analysed on ITT-worst case population. All tests were two-sided and used the 0.05 level to declare significance.

Results

Subject disposition and baseline characteristics

A total of 136 subjects were enrolled in this study. They were re-randomised to receive either adapalene gel 0.1% (73 subjects) or its gel vehicle (63 subjects; ( figure 1 )). One subject in the adapalene group had missing data from the initial study starting point and was therefore not included in the efficacy analysis. Subject disposition was similar between the two treatment groups. Discontinuation rates were higher in the vehicle group (20.6%) relative to the adapalene group (6.8%). The most common reason for discontinuation was subject request (2.7% and 14.3% for the adapalene and vehicle groups, respectively). A total of 118 subjects (87%) completed the study.

Baseline subject characteristics of the ITT population are summarised in table 1( Table 1 ). Demographic characteristics and baseline dermatological scores were comparable between the two treatment groups. There were slightly more females (63.5% vs. 53.4%), more Caucasians (90.5% vs. 84.9%), and slightly fewer subjects with mild baseline acne (76.2% vs. 86.3%) in the vehicle group relative to the adapalene group.
Table 1 Subject demographics and baseline disease characteristics (ITT population)

	Adapalene Gel 0.1% n = 73	Gel Vehicle n = 63	Total n = 136
Demographics
Gender
Female	39 (53.4%)	40 (63.5%)	79 (58.1%)
Male	34 (46.6%)	23 (36.5%)	57 (41.9%)
Race
Black/Negroid	8 (11.0%)	4 (6.3%)	12 (8.8%)
Other or mixed	1 (1.4%)	2 (3.2%)	3 (2.2%)
White/Caucasoid	62 (84.9%)	57 (90.5%)	119 (87.5%)
Yellow/Mongoloid	2 (2.7%)	–	2 (1.5%)
Skin phototype
I	3 (4.1%)	1 (1.6%)	4 (2.9%)
II	19 (26.0%)	23 (36.5%)	42 (30.9%)
III	27 (37.0%)	23 (36.5%)	50 (36.8%)
IV	15 (20.5%)	9 (14.3%)	24 (17.6%)
V	4 (5.5%)	3 (4.8%)	7 (5.1%)
VI	5 (6.8%)	4 (6.3%)	9 (6.6%)
Age (in years)
Mean±STD	19.1 ± 5.56	18.6 ± 4.31	18.9 ± 5.01
Median	17.9	17.3	17.5
(Min,Max)	(13,45.1)	(12.2,31.3)	(12.2,45.1)
Disease characteristics at starting point of combination study
Lesion count
Total
Mean	101.1	99.7	–
Median	80.0	74.0	–
Inflammatory
Mean	33.6	32.9	–
Median	27.5	28.0	–
Noninflammatory
Mean	67.6	66.8	–
Median	48.5	40.0	–
Global severity grade (Revised Leeds Scale)
4-7: moderate	64 (87.6%)	59 (93.5%)	–
5-8: moderately severe	9 (12.3%)	4 (6.4%)	–
Disease characteristics at starting point of maintenance study
Median^a percent reduction in lesion count
Total	72.5%	69.2%	–
Inflammatory	76.2%	75.0%	–
Noninflammatory	71.3%	66.7%	–
Global severity grade (Revised Leeds Scale)
1-3: mild	63 (86.3%)	48 (76.2%)	–
4-7: moderate	10 (13.7%)	15 (23.8%)	–

^aDistribution of lesion % reduction being skewed, it was estimated using the median.

Efficacy evaluation

The maintenance success rates for total, inflammatory, and non inflammatory lesion counts at end point (week 12, ITT population, worst case) are shown in ( figure 2 ). These rates reflect the percentage of subjects maintaining at least 50% of improvement from the previous combination study. After 12 weeks, maintenance treatment with adapalene gel 0.1% resulted in higher success rates in total (84.7% vs. 63.5%; P = 0.0049), inflammatory (76.4% vs. 66.7%; P = 0.21), and non inflammatory (84.7% vs. 55.6%; P < 0.001) lesions compared to treatment with vehicle ( (figure 2) ). The same trend in favour of adapalene gel 0.1% was observed for the percent reduction from initial state in lesion counts ( (figure 3) ).

For the global severity assessment, at baseline, 86.3% in the adapalene group and 76.2% in the vehicle group had mild acne (Leeds global severity score 1 to 3). Global severity remained stable in the adapalene group, whereas it worsened slightly in the vehicle group: at the end of the study, 82.2% vs. 68.3% of subjects presented mild acne and 17.8% vs. 31.7% of subjects presented moderate acne for the adapalene and vehicle groups, respectively; P = NS. ( Figure 4 ) illustrates the effect of 12 weeks of maintenance therapy with adapalene gel 0.1% following 12 weeks of combination therapy with adapalene gel 0.1% plus lymecycline on moderate to moderately severe facial acne lesions.

Safety evaluation

Severity scores for erythema, scaling, dryness, and stinging/burning are summarised graphically in ( figure 5 ). As expected, local cutaneous tolerability of study treatments was excellent for both groups. Mean tolerability scores for erythema, scaling, dryness, and stinging/burning were less than 1 (mild) for all study visits. Worst scores at any time during the study for these tolerability parameters were also all less than 1 (mild). Most subjects in both groups experienced mild or no irritation.

The number of subjects experiencing adverse events was similar in both treatment groups: 25% and 22% for the adapalene and vehicle groups, respectively. A total of 5 treatment-related adverse events occurred in 4 (5.5%) of the adapalene subjects (adverse events: headache [2]), eczema [2], and erythema & desquamation [1]). Two of these adverse events were severe (eczema and erythema & desquamation). There were no treatment related adverse events in the vehicle group. One subject in the vehicle group experienced a serious adverse event deemed unrelated to study treatment (wisdom teeth extraction). There were 2 adverse events in the adapalene group that led to study discontinuation; skin infection (unlikely related) and erythema & desquamation (related).

Discussion

The goal of maintenance therapy is the prevention of the recurrence of acne lesions through the suppression of subclinical microcomedones [5, 6]. Currently, there are relatively few studies available to help guide evidence based decisions for the long-term management of this disease. The current study adds to our limited, but growing foundation of clinical data supporting the potential of maintenance therapies with topical retinoids. In this 12-week study, adapalene gel 0.1% was evaluated as a maintenance therapy in subjects who showed at least moderate improvement in their moderate to moderately severe acne in a previous 12-week adapalene-lymecycline combination therapy study [24].

Overall, the results of this study demonstrate a clinical benefit of continued adapalene use as a maintenance therapy for acne. Adapalene provided numerically better results relative to gel vehicle for all efficacy assessments, including maintenance success rates, global severity, global improvement from baseline, and the percent reduction in lesion counts (total, inflammatory, and non inflammatory) from baseline of the previous combination study. At week 12, adapalene was significantly superior relative to the vehicle for success rates of total and non inflammatory lesions. A “success” was defined as a subject maintaining at least 50% of improvement from the previous study, with missing data considered as a failure (worst case). Adapalene was safe and well tolerated during this study, consistent with its well-documented profile [19-23].

The results of the current study confirm data observed in previous maintenance studies [8-10]. In a previous 16-week study, Thiboutot and colleagues evaluated the maintenance effect of adapalene gel 0.1% relative to its gel vehicle in those subjects who showed at least moderate improvement in their severe acne from the previous adapalene-doxycycline combination therapy study [10, 27]. After 16 weeks of treatment, adapalene provided statistically significantly superior results relative to gel vehicle for all efficacy assessments, including maintenance success rates for total, inflammatory and non inflammatory lesions (same maintenance definition as the current study). In the Thiboutot study, a statistically significant difference between adapalene and vehicle was first observed at 4 months. This observation may reflect the time for the recurrence of visible acne based on the natural life cycle of a comedone. Since these studies were not evaluating the presence of subclinical microcomedones, the evaluations in both these studies are limited to assessment of visible acne. Also, all subjects received oral antibiotics in previous combination therapy studies, so the antibiotic clearance time may have also affected the time for acne recurrence. It is noteworthy that the current study was only 12 weeks and therefore, based on the results of the Thiboutot 16-week maintenance study, we may expect to observe additional benefit with a longer study duration. These results confirm those seen in recent open-label adapalene maintenance studies [8, 9].

Despite the rising recommendations on the use of retinoids for acne maintenance therapy [29], to our knowledge, no formal definition of acne maintenance currently exists. In our study, like in the Thiboutot study, it was agreed that maintaining at least 50% improvement from a previous acute combination therapy would represent the most realistic and easy criterion to measure the efficacy of an acne maintenance treatment. This was based on the definition of psoriasis relapse as proposed by a medical advisory group [30, 31].

Together with the results of previous combination and maintenance studies, these results support recommendations of recent consensus guidelines from the Global Alliance to Improve Outcomes in Acne [5, 8-10, 24, 26, 27]. The report states that an effective strategy for the treatment of moderate to severe acne is to utilise combination therapy at the onset of therapy with both a topical retinoid and an oral antibiotic until reasonable clearing has occurred. Then, the antibiotic therapy should be discontinued to reduce the potential for developing resistance and the topical retinoid continued to prevent recurrence. The guidelines consider topical retinoids as the cornerstone of acne treatment, alone or in combination, for all but the most severe cases of acne.

Topical retinoids have been associated with elevated skin irritation, so careful consideration must be given to the tolerability of a potential maintenance therapy. Cutaneous side effects may decrease the likelihood of treatment adherence, particularly when treating an “asymptomatic” condition [32]. Among the currently available topical retinoids, adapalene is considered the best tolerated therapy [33-35], and therefore is a rational choice for maintenance therapy. Of the topical retinoids, adapalene has the most robust data with the largest number of subjects studied in long-term treatment [8-10]. Avoiding complicated treatment regimens is also desirable for a maintenance therapy. In contrast to some treatments, special treatment/washing regimens [36, 37] are not necessary with adapalene use, which is well tolerated even if applied immediately after washing [38].

In summary, this study has demonstrated a clear clinical benefit of continued treatment with adapalene gel 0.1% as a maintenance therapy for acne. Together with data from previous studies, these results suggest adapalene should be used initially with antibiotic therapy in moderate to moderately severe acne and then continued for the long-term management of this disease to ensure acne lesions remain in remission.

Acknowledgements

The authors would like to thank the following investigators: Patrice Belperon, Angers, France; Isaac Bodokh, Cannes, France; Alexandre Brunet, Angers, France; Elie Cattan, Pantin, France; William Cunliffe, Leeds UK; Louis Dubertret, Paris, France; Dr Colin John Fleming, Dundee, UK; Dr Bruno Haliloua, Paris, France; Jean-Marie La Chapelle, Brussels, Belgium; Dr Julien Lambert, Edegem, Belgium; Jean Meynadier, Montpellier, France; Dr. Gilles Rostain, Nice, France; Mireille Ruer-Mular, Martigues, France; as well as David Cox for editorial assistance.

Financial support: This study was funded by Galderma R&D, Sohpia Antipolis, France

Conflict of interest: The investigating institutions received payments for this research study. Three of the authors are employees of Galderma (Kerrouche, Sidou and Soto)

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