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Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials
SUPPORTED BY AN EDUCATIONAL GRANT FROM GALDERMA LABORATORIES, INC.
Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials W. J. Cunliffe, M D , a R. Caputo, ]VID, b B. Dreno, MD, c L. F6rstr6m, MD, d M, Heenen, MD, e C. E. Orfanos, MD, f Y. Privat, MD,g A. Robledo Aguilar, MD, h J. Meynadier, i Mohsen Alirezai, MD, i S. Jablonska, MD,J A. Shalita, MD, k J. S. Weiss, MD, 1 D. K. Chalker, MD, m C. N. Ellis, MD, n A. Greenspan, MD, ° H. I. Katz, MD,P I. Kantor, MD,q L. E. Millikan, MD, r J. M. Swinehart, MD, s L. Swinyer, MD, t C. Whitmore, MD, u J. Czernielewski, MD, v and M. Verschoore, M D v Leeds, United Kingdom; Milano, Italy;
Nantes, Aixen Provence, Montpellier, and Levallois-Perret, France; Helsinki, Finland; Brussels, Belgium; Berlin, Germany; Madrid, Spain; Warsaw, Poland," Brooklyn, Port Chester and Great Neck, New York; Atlanta and Augusta, Georgia; Ann Arbor, Michigan; Maywood, New Jersey; Fridley, Minnesota; New Orleans, Louisiana; Denver, Colorado; Salt Lake City, Utah; and Lynchburg, Virginia Background: Adapalene is a new chemical entity that exhibits tretinoin-like activities in the terminal differentiation process. Objective: We evaluated a dose range effect of two concentrations of adapalene gel as acne treatment and compared adapalene 0.1% gel with trefnoin 0.025% gel in the treatment of acne patients in two large mtdticenter studies. Methods: Multicenter, investigator-masked, parallel group studies including 89 acne patients in the dose range study and 591 patients in the concurrent controlled studies were conducted. Results: Adapalene gel 0.1% was significantly more effective in treating acne lesions than 0.03% adapalene gel. Adapalene gel 0.1% was significantly more effective than 0.025% or tretinoin gel in one study and of the same effectiveness in the other study. Adapalene gel was always better tolerated than tretinoin gel. Conclusion: Adapalene 0.1% gel is a safe and effective treatment of acne vulgaris. (J Am Acad Dermatol 1997;36:S126-34.) From the General Infirmary, Leedsa; the Instituto di Scienze Dermatologiche, Milanob; the Service de Dermatologie, H6tel Dieu,NantesC;the Department of Dermatology, University Central Hospital, Helsinkid; the Service de Derrnatologie, H6pital Erasme, Bmsselse; the Department of Dermatology, University Medical Center Benjamin Franklin, Berlinf; the Centre Carnot Forbin, Aix en Provenceg; the Catedratico de Dermatologia, Hospital Clinico Universitario, Madridh; the Clinique de Dermatologie, C.H.U. de Montpellier, H6pital Saint Charles, Montpelliexa;the Klinika Demaatologiczna A.M., WarsawJ; the SUNY Health Science Center, Brooklyn, and the/ntemational Research Services, Port Chesterk; Emory University, Aflantal; the Medical College of Georgia, Augustam; the University of Michigan, Ann Arborn; TKL Research, Maywood°; the Minnesota Clinical Study Center, FridleyP; the Research Testing Laboratories, Inc., Great Neckq; Tulane University New Orleansr; the Colorado Medical Research Center, DenvelS; Salt Lake Cityt; the Education and Research Foundation, LynchburgU; and the Laboratoires Galderma, Levallois-Perret.v Reprint requests: M. Verschoore, MD, Laboratoires Galderma, 20 Avenue Andr6 Malraux, 92309 Levallois-Perret Cedex, France. Copyright © 1997 by the American Academy of Dermatology, Incl 0190-9622/97/$5.00 + 0 16/0/81181
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Adapalene possesses some of the biological activities of tretinoin, but has distinct physicochemical properties. The most characteristic are its increased chemical and light stability, rigidity, and high lipophilicity, a, 2 In addition, its affinity profile for the nuclear and cytosolic retinoic acid receptors is unlike that of tretinoin o1"isotretinoin. Tretinoin binds to the cytosolic retinoic acid binding protein with high affinity, but adapalene does not bind at all) Tretinoin has similar, high affinity to all the nuclear retinoic acid receptors (RARs oL, [3, and ~); adapalene, in conwast, has selective affinity for RAR-[3 and RAR-~/. 4-7 A human clinical pharmacology study was performed in 25 subjects treated with 0.1% adapalene gel or 0.1% tretinoin cream under occlusion for 4 days. s Ortly retinoic acid-treated sites showed
Journal of the American Academy of Dermatology Volume 36, Number 6, Part 2
erythema, spongiosis, and hyperplasia. However, both adapalene and tretinoin caused significant elevation o f the cytosolic retinoic acid binding protein-II m R N A . Early clinical study confirmed the efficacy o f adapalene in lotion vehicle for the treatment of acne. 8 The human pharmacologic study 9 and initial pilot clinical efficacy and safety comparison of tretinoin and adapalene gel in acne patients 1° suggested a superior safety profile and at least similar if not better efficacy of adapalene over tretinoin. Three studies were designed to select the most effective adapalene concentration for acne treatment and to compare the efficacy and safety of adapalene gel at the selected concentration with tretinoin gel.
DOSE RANGE STUDY: STUDY I Patients and methods This controlled study was performed in two centers on two parallel groups. Patients received, according to a predetermined randomization scheme using the Latin square method, one of three treatments: 0.03% adapalene gel, 0.1% adapalene gel, or 0.025% trefinoin gel. In view of the different physical appearance of the tested formulations, the treatments were dispensed by someone other than the investigator and therefore investigators were blinded to treatment assignment. Treatments were applied to ache sites on a dry face daily, 1 hour before bedtime, for 12 weeks. If necessary, the test material was also applied to other acne sites such as the shoulders, chest, or back. The subjects enrolled in this study were of both sexes, were 12 to 30 years old and lead mild to moderate acne (1 to 5 on Burke and Cunliffe' s scale), 11 with a minimum of 20 comedones and 10 facial inflammatory lesions. Patients with secondary or severe acne were not included. Patients who had been treated for acne with systemic retinoids during a 6-month period before the initiation of the study, or by systemic antibiotics (except penicillha), systemic or topical anfiinflammatories during the preceding 4 weeks, or by a topical treatment during the preceding 2 weeks were also excluded. The study was conducted from November 1988 through May 1989, following guidelines in accordance with the Helsinki Statement and approved by the Ethical Committee of the Montpellier-Ntmes C.H.U. All patients (as well as their parents or guardians, if they were minors) signed informed consent guidelines written in the respective language of each center after detailed explanation of the guidelines. This study was performed according to the Good Clinical Practices and the Good Laboratory Practices in the centers of Montpelller, France (investigator: J. Meynadier) and Warsaw, Poland (investigator: S. Jablonska).
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Treatments The evaluated products were 0.1% adapalene gel or 0.03% adapalene aqueous gel and a 0.025% tretinoin gel (all-trans retinoic acid). All treatments were supplied in identical 30 gm tubes. The treatments were not given to the patients by the investigator, but by an assistant, and patients were asked not to talk about the product appearance with the investigator. The patients were authorized to use their usual hygiene products (except as~ingent and alcohol-containing products).
Efficacy evaluation At each follow-up visit (inclusion visit, and weeks 1, 2, 4, 8, and 12), noninflammatory and inflammatory lesions (open and closed comedones, papules, pustules, nodules, and cysts) were counted on the forehead, the right and left cheeks, and the chin. The main outcome of this study was a change in the acne lesion number. A global score of patient acne was also established by the investigator on a scale from 0 to 10 according to the Burke and Cunllffe method. 11 For this purpose, each investigator was supplied with characteristic photographs of the different acne severity scores.
Safety evaluation Facial cutaneous tolerance was evaluated before the first application of the treatment and at Weeks 1, 2, 4, 8, and 12. The features taken into account were erythema, cutaneous dryness, scaling, burning, and pruritus. The first three were evaluated by the investigator. Pruritus and burning were evaluated by the patients themselves at two levels: Chronic reaction persisting between the applications, and temporary reaction occurring only after application. All these features were evaluated on a scale graduated from 0 to 3, in which 0, 1, 2, and 3 corresponded to no sensation, light or hardly perceptible, moderate, and severe sensation, respectively. In the case of an abnormally severe erythema or irritation that might be caused by treatment and constitute a case of contact dermatitis, test patches containing the different components of the formula were provided. Unexpected medical events and concomitant treatments were also noted.
CONCURRENT CONTROLLED STUDIES Patients and methods Study II: Adapalene 0.1% versus tretinoin, U.S. multicenter controlled study This U.S. multicenter randomized, investigator-masked trial was designed to compare the efficacy and safety of adapalene gel 0.1% with tretinoin gel 0.025% in the treatment of acne vulgaris. The study was performed by the following main investigators: A. Shalita (Brooklyn, NY), J.S. Weiss (Atlanta, GA), D.K. Chalker (Augusta, GA), C.N. Ellis (Ann Arbor, MI), A. Greenspan (May-
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Fig. 1. Reduction of total number of lesions during 12 weeks of treatment with 0.03% adapalene gel (diamonds), 0.1% adapalene gel (squares), an 0.025% tretinoin gel (triangles). (Figure from the article "Etude comparative de l'efficacit6 et de la tolrrance de gels d' adapalene ~ 0,1 et 0,003M et d'un gel de trrtinoine ~ 0, 025% dans le traitement de l'acne." M. Alirezai, J. Meyndier, S. Jablonska, J. Czemielewsli, M. Verschoore. Ann Dermatol Venereol, 1996;123:165-70. Reproduced with authorization of the Editing Committee, Copyright Masson Paris.)
wood, NJ), H.I. Katz (Fridley, MN), I. Kantor (Great Neck, NY), L.E. Millikan (New Orleans, LA), T. Swinehart (Denver CO), L. Swinyer (Salt Lake City, LIT), and C. Whitmore CLynchbttrg, VA). Inclusion criteria were identical to Study I. Three huntired twenty-three patients, 12 to 30 years old with global grades 13[ and 1B acne vulgaris were enrolled (approximately 30 patients per study center). The methods for evaluating efficacy and safety were identical to Study I. Laboratory evaluations for standard clinical chemistries, hematology, and urinalysis were performed in two study centers before and after a 3 month treatment period.
Study HI: Adapalene 0.1% versus tretinoin, European rnulticenter controlled study The European study was performed according to a multicenter, randomized, parallel group, investigatormasked design and followed the same method as Study I. The study was conducted in accordance with the Declaration of Helsinki, and written informed consent in the local language for each study center was obtained from the patients (and from their parents or guardian in the case of minors) after the procedure had been fully explained. The investigations were performed in accordance with good clinical practice and good laboratory practice. The results presented in this report are drawn from patients studied in eight centers located in seven different countries, the principal investigators of which were: W.J. Cunliffe (Great Britain); C.E. Orfanos and H. Gollnick (Germany); R. Caputo and C. Rigoni (Italy); L. FrrstrOm
Fig. 2. Mean percentage reduction in total lesion counts during 12-week treatment period. (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
(Finland); M. Heenen and D. Parent (Belgium); Y. Privat, P. Berbis, and C. Dufo (France); B. Dreno (France); A. Robledo Aguilar and E. Lopez Bran (Spain).
Treatments Study H and Study IH For both studies the lreatment method was the same. The products evaluated were a 0.1% (w/w) adapalene aqueous gel and a marketed 0.025% (w/w) tretinoin gel. The two treatments were supplied in identical 45 gm tubes. Directions for appfication were the same for the two treatments. As the two gels were physically different in appearance, the treatments were dispensed by someone other than the investigator, usually the investigator's assistant.
Efficacy evaluation Study II and Study HI For both studies the method applied was the same as in Study I. Patients were evaluated five times during the study period for efficacy and safety: At baseline and at weeks 2, 4, 8, and 12. The last available evaluation (either at week 12, or earfier for patients who did not complete the study) is referred to as endpoint. At each visit, individual noninflammatory and inflammatory lesions (open and closed comedones, papules, pustules, and nodules) on the forehead, the right and left cheeks, and the chin were counted. A global evaluation of the patients' ache condition was also performed by the investigator using a severity scale ranging from 0 to 10. This rating was based on a comparison with a series of representative photographs following the Leeds technique developed by Burke and Cunliffe. 1° Safety evaluation Study lI and Study HI For both studies the method applied was the same as in Study I. Adverse reactions were evaluated at each visit (i.e., at baseline and at weeks 2, 4, 8, and 12). Facial skin
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Fig. 4. Mean percentage reduction in inflammatory lesion counts during 12-week treatment period. (From Shalita A, et al. J Am Acad Dermatol 1996;34:482,5).
Table I. Evolution of acne lesions (average number and percentage reduction) for tretinoin and adapalene gel Average number
Average number
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Non-inflammatory lesions Tretinoin 0.025% Adapalene 0.1% Inflammatory lesions Tretinoin 0.025% Adapalene 0.1% Global score Tretinoin 0.025% Adapalene 0.1%
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safety evaluation was based on the assessment of erythema, dryness, scaling, burning, and pruritus. The first three were evaluated by the investigator. Pruritus and burning were evaluated by the patients themselves, in two ways: Either as a chronic, persistent response between applications of treatment, or as a transient response, immediately after application. All of these features were ranked on a scale ranging from 0 to 3 where 0, 1, 2, and 3 corresponded to none, mild or barely perceptible, moderate, and severe, respectively. Unexpected medical events and concomitant therapy were also recorded. Adapalene plasma levels were determined at the last visit in 32 patients treated on large skin areas. The analytical method used was a reverse phase high pressure liquid chromatography (HPLC).
RESULTS: STUDIES I, II, III 1) Study I: Dose range study results A total of 89 male and female patients were included in Study I; 45 in Montpellier and 44 in Warsaw. In total, 29 patients received 0.03% ada-
palene gel, 30 patients 0.1% adapalene gel, and 30 patients 0.025% tretinoin. During the study, eight dropouts occurred: three for ineffectiveness after 8 weeks of treatment, and five for reasons not related to treatment. A regular decrease in the number of acne lesions was observed during the study in the three comparative groups of patients (Fig. 1). A dose range effect was observed for the two concentrations of adapalene; 0.03% was the least effective on inflamed lesions (p < 0.01, week 12), total acne lesion counts (p < 0.01 week 12), and global acne score (p < 0.05 at week 8 a n d p < 0.01 at week 12) (Table I). The low concentration of adapalene 0.03% gel was less effective than tretinoin in reducing noninflamed lesions (p < 0.05 at week 4 and week 8). The percent of patients experiencing more than 50% reduction of total acne lesions was 76% in the adapalene 0.03% group, 90% in the adapalene 0.1% group and 93% in the tretinoin group. The three products induced skin irritation, al-
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Fig. 7. Mean percentage of patients at each visit experiencing dryness graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
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Fig. 6. Mean percentage of patients at each visit having scaling graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5).
though there were significant differences (p < 0.05) in intensity in favor of adapalene for erythema, scaling~ and burning.
2) Study II: Adapalene 0.1% versus tretinoin multicenter controlled study (U.S. study) 12 Of the 323 patients enrolled, 288 (149 adapalene, 139 tretinoin) completed through week 12 while the remaining 35 discontinued. Of these, 25 patients discontinued for nonmedical reasons and 10 because of medical events: four were in the adapalene gel group (two cases of acne flare, two cases of skin irritation) and six in the trefinoin gel group (one case of acne flare, one case of skin irritation, two cases of skin dryness, one case of herpes zoster, and one case
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Fig. 8. Mean percentage of patients at each visit experiencing burning graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
of skin infection). In total, 323 patients were evaluable for safety and 290 for efficacy. The mean baseline lesion counts were not significantly different between the treatment groups (82.1 and 85.3 total lesions in adapalene and tretinoin group, respectively). Adapalene gel produced greater reductions in noninflammatory, inflammatory, and total lesion counts than tretinoin gel at week 12. The mean percent reduction in these types of lesions was as follows: 49% versus 37% for total lesions (p < 0.01), 46% versus 33% for noninflammatory (p=0.02), 48% versus 38% for inflammatory (p = 0.06) (Figs. 2 through 4). The number of patients treated with adapalene gel who experienced excellent improvement at week 12 was significantly greater (p < 0.05) for noninflammatory lesions (31%
Journal of the American Academy of Dermatology Volume 36, Number 6, Part 2
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vs 18%) and total lesions (29% vs 18%), but not for inflamrnatory lesions (32% vs 22%). The local irritation experienced, especially dnring the early stages of treatment, was typical of topical retinoid therapy. Irritation was, in general, mild for both treatments. There were significantly fewer (p < 0.05) incidents and a lesser degree of erythema, scaling, dryness, and burning throughout the study in the adapalene gel group (Figs 5 through 8).
Laboratory evaluations were performed in 54 patients before and after 3 months of treatment. No clinically significant changes were observed.
3) Study III: Adapalene 0.1% versus tretinoin multicenter controlled study (European study) A total of 268 patients were enrolled into the study, with 134 assigned to receive treatment with adapalene gel (74 males and 60 females, mean age 19.7 years, range 12 to 30 years) and 134 to tretinoin gel (69 males and 65 females, mean age 19.2 years, range 12 to 28 years). There were no significant differences between treatment groups in the study population with regard to age, sex, and skin complexion. A total of 32 patients did not complete the study. Eight of them (three in the adapalene group and five in the tretinoin group), were lost to follow-up or dis-
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Fig. 13. Percent of patients with moderate and severe burning, Study lB.
Fig. 15. Acne patient treated by adapalene 0.1% gel (after treatment), Study lB.
Fig. 14. Acne patient treated by adapalene 0.1% gel (before treatment), Study lB. continued for noncompliance with the protocol after the first visit (week 0). One patient in the tretinoin group was discontinued after the week 2 visit. The other 23 patients (10 in the adapalene group and 13
in the tretinoin group) were considered evaluable for efficacy because their treatment discontinuation took place after the week 4 visit. Therefore, of the 268 enrolled patients, 259 were deemed evaluable for efficacy (131 in the adapalene group and 128 in the tretinoin group), and 236 completed the 12 week study (121 in the adapalene group and 115 in the tretinoin group), In the two treatment groups, a regular decrease in acne lesion counts was observed as a function of time for all four features, with a maximum change close to 60% at week 12. One patient treated with adapalene was completely clear of lesions at week 8. No statistically significant differences between treatments were associated with any of these features at any of the evaluation points. Mean inflammatory and noninflammatory lesion counts also tended to decrease more rapidly in the adapalene-treated group than in the tretinoin-treated group at week 2 (Figs. 9 and 10). When patient groups were compared
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Fig. 16. Acne patient treated by adapalene 0.1% gel (before treatment), Study lB.
Fig. 17. Acne patient treated by adapalene 0.1% gel (after treatment), Study 11I.
according to their degree of reduction in each feature relative to baseline, the percentage of patients who experienced a more than 50% decrease in total lesion counts at week 12 was 72% in the adapalene group and 75% in the tretinoin group. Seven patients were discontinued from therapy because of treatment failure. Two were in the adapalene group and five in the tretinoin group. At baseline, the scores of all features taken into account for evaluating safety were similar between treatments. At each subsequent time point, the mean scores for all of the tolerance features, except persistent pruritus, were slightly higher than baseline in both treatment groups, increasing to a maximal value at week 2, and then steadily decreasing. When adapalene and tretinoin gels were compared, significantly lower mean scores (p < 0.05) were obtained with adapalene for the following features: burning after application (weeks 2 to 12, p < 0.01), persistent burning (week 8), pruritus after application (week
12), and dryness and scaling (weeks 8 and 12) (Figs 11 through 13). Mean erythema scores were not significantly different between treatments. Dosage regimen alterations for skin safety reasons were required in 19 patients treated with adapalene gel and in 29 patients treated with tretinoin gel. DISCUSSION
The efficacy of tretinoin for the treatment of acne vulgaris has been demonstrated in several studies comparing 0.1%, 0.05 %, and 0.025 % concentrations in various vehicles to the vehicle aloneJ 3 To determine the efficacy of adapalene gel, the highest commercially available strength of tretinoin gel was chosen. For this reason, adapalene gel 0.1% was compared with tretinoin gel 0.025% in two large multicenter trials. After a 12-week treatment of patients with mild to moderate acne vulgaris (grades 1 to 5 global facial acne score), adapalene 0.1% gel proved to be as ef-
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fective as tretinoin 0.025% gel in one study and significantly more effective than tretinoin gel in another. Clinical results of adapalene treatment are shown in Figs. 14 through 17. No systemic effects were observed with either of the tested products. Adapalene 0.1% gel induced mild skin irritation, increasing in intensity to a maximum at week 2 of treatment before regularly decreasing to week 12. The irritation intensity with adapalene 0.1% gel was significantly lower than with tretinoin gel for the following: Burning after application, persistent buming, pruritus after application, dryness, and scaling. No patients treated with adapalene gel discontinued therapy because of side effects, as opposed to four patients receiving tretinoin gel (all with an erythematous eruption). Fewer patients receiving adapalene (19 vs 29) altered the dosage for safety reasons. We conclude that topical 0.1% adapalene gel is an effective, safe and well-tolerated treatment for acne vulgaris, resulting in low systemic exposure and no detectable systemic toxicity. It is as effective as topical tretinoin and has a superior skin safety profile. REFERENCES 1. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol 1993;6Supp. L:61-9. 2. Elbaum DJ. Comparison of the stability of topical isotretinoin and topical tretinoin and their efficacy in acne. J Am Acad Dermatol 1988;19:486-91. 3. Asselineau D, Cavey MT, Shroot B, et al. Control of epi-
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11. 12.
13,
dermal differentiation by a retinoic acid analogue unable to bind cytosofic 1-elinoic acid binding proteins (CRABP). J Invest Dermatol 1992;8:128-34. Shroot B, Bemard0n JM, Charpentier B, et al. New retinoids exhibiting selectivity for the nuclear retinoic acid receptor RAR[3. J Invest Dermatol 1991;96:577A. Reichert U, Bernardon JM, Charpentier B, et al. Synthetic retinoids: receptor selectivity and biological activity. In: Bernard BA, Shroot B, editors. Pharmacology and the skin, Vol 5: From molecular biology to therapeutics. 1993:11727. Redfem CPF. Molecular makers of retinoid activity in the skin. J Invest Derrnatol 1994;102:11-2. Fogh K, Voorhees JJ, Astrom A. Expression, purification and binding properties of human cellular retinoic acidbinding protein type I and type IL Arch Biochem Biophys 1993;300:751-5. Verschoore M, Langner A, Wolska H, et al. Vehicle controlled study of CD 271 lotion in the topical treatment of acne vulgaris. J Invest Dermatol 1993;100:221A. Gfiffiths CEM, Elder JT, Bernard BA, et al. Comparison of CD 27l (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression [Abstract]. J Invest Dermatol 1993; 101:325-8. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol 1991;124:368-71. Burke BM, Ctmliffe WJ. The assessment of acne ,/aflgaris--the Leeds technique: Br J Dermatol 1984; 111:83-92. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.l % and tretinoin gel 0.025% in the treatment of ache vulgaris: A multicenter trial. J Am Acad Dermatol 1996;34:482-5. Mandy SA, Thome EG. A comparison of the efficacy and safety of tretinoin cream 0.025% and 0.05%. Advances in Therapy 1990;7:94-9.
Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials W. J. Cunliffe, M D , a R. Caputo, ]VID, b B. Dreno, MD, c L. F6rstr6m, MD, d M, Heenen, MD, e C. E. Orfanos, MD, f Y. Privat, MD,g A. Robledo Aguilar, MD, h J. Meynadier, i Mohsen Alirezai, MD, i S. Jablonska, MD,J A. Shalita, MD, k J. S. Weiss, MD, 1 D. K. Chalker, MD, m C. N. Ellis, MD, n A. Greenspan, MD, ° H. I. Katz, MD,P I. Kantor, MD,q L. E. Millikan, MD, r J. M. Swinehart, MD, s L. Swinyer, MD, t C. Whitmore, MD, u J. Czernielewski, MD, v and M. Verschoore, M D v Leeds, United Kingdom; Milano, Italy;
Nantes, Aixen Provence, Montpellier, and Levallois-Perret, France; Helsinki, Finland; Brussels, Belgium; Berlin, Germany; Madrid, Spain; Warsaw, Poland," Brooklyn, Port Chester and Great Neck, New York; Atlanta and Augusta, Georgia; Ann Arbor, Michigan; Maywood, New Jersey; Fridley, Minnesota; New Orleans, Louisiana; Denver, Colorado; Salt Lake City, Utah; and Lynchburg, Virginia Background: Adapalene is a new chemical entity that exhibits tretinoin-like activities in the terminal differentiation process. Objective: We evaluated a dose range effect of two concentrations of adapalene gel as acne treatment and compared adapalene 0.1% gel with trefnoin 0.025% gel in the treatment of acne patients in two large mtdticenter studies. Methods: Multicenter, investigator-masked, parallel group studies including 89 acne patients in the dose range study and 591 patients in the concurrent controlled studies were conducted. Results: Adapalene gel 0.1% was significantly more effective in treating acne lesions than 0.03% adapalene gel. Adapalene gel 0.1% was significantly more effective than 0.025% or tretinoin gel in one study and of the same effectiveness in the other study. Adapalene gel was always better tolerated than tretinoin gel. Conclusion: Adapalene 0.1% gel is a safe and effective treatment of acne vulgaris. (J Am Acad Dermatol 1997;36:S126-34.) From the General Infirmary, Leedsa; the Instituto di Scienze Dermatologiche, Milanob; the Service de Dermatologie, H6tel Dieu,NantesC;the Department of Dermatology, University Central Hospital, Helsinkid; the Service de Derrnatologie, H6pital Erasme, Bmsselse; the Department of Dermatology, University Medical Center Benjamin Franklin, Berlinf; the Centre Carnot Forbin, Aix en Provenceg; the Catedratico de Dermatologia, Hospital Clinico Universitario, Madridh; the Clinique de Dermatologie, C.H.U. de Montpellier, H6pital Saint Charles, Montpelliexa;the Klinika Demaatologiczna A.M., WarsawJ; the SUNY Health Science Center, Brooklyn, and the/ntemational Research Services, Port Chesterk; Emory University, Aflantal; the Medical College of Georgia, Augustam; the University of Michigan, Ann Arborn; TKL Research, Maywood°; the Minnesota Clinical Study Center, FridleyP; the Research Testing Laboratories, Inc., Great Neckq; Tulane University New Orleansr; the Colorado Medical Research Center, DenvelS; Salt Lake Cityt; the Education and Research Foundation, LynchburgU; and the Laboratoires Galderma, Levallois-Perret.v Reprint requests: M. Verschoore, MD, Laboratoires Galderma, 20 Avenue Andr6 Malraux, 92309 Levallois-Perret Cedex, France. Copyright © 1997 by the American Academy of Dermatology, Incl 0190-9622/97/$5.00 + 0 16/0/81181
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Adapalene possesses some of the biological activities of tretinoin, but has distinct physicochemical properties. The most characteristic are its increased chemical and light stability, rigidity, and high lipophilicity, a, 2 In addition, its affinity profile for the nuclear and cytosolic retinoic acid receptors is unlike that of tretinoin o1"isotretinoin. Tretinoin binds to the cytosolic retinoic acid binding protein with high affinity, but adapalene does not bind at all) Tretinoin has similar, high affinity to all the nuclear retinoic acid receptors (RARs oL, [3, and ~); adapalene, in conwast, has selective affinity for RAR-[3 and RAR-~/. 4-7 A human clinical pharmacology study was performed in 25 subjects treated with 0.1% adapalene gel or 0.1% tretinoin cream under occlusion for 4 days. s Ortly retinoic acid-treated sites showed
Journal of the American Academy of Dermatology Volume 36, Number 6, Part 2
erythema, spongiosis, and hyperplasia. However, both adapalene and tretinoin caused significant elevation o f the cytosolic retinoic acid binding protein-II m R N A . Early clinical study confirmed the efficacy o f adapalene in lotion vehicle for the treatment of acne. 8 The human pharmacologic study 9 and initial pilot clinical efficacy and safety comparison of tretinoin and adapalene gel in acne patients 1° suggested a superior safety profile and at least similar if not better efficacy of adapalene over tretinoin. Three studies were designed to select the most effective adapalene concentration for acne treatment and to compare the efficacy and safety of adapalene gel at the selected concentration with tretinoin gel.
DOSE RANGE STUDY: STUDY I Patients and methods This controlled study was performed in two centers on two parallel groups. Patients received, according to a predetermined randomization scheme using the Latin square method, one of three treatments: 0.03% adapalene gel, 0.1% adapalene gel, or 0.025% trefinoin gel. In view of the different physical appearance of the tested formulations, the treatments were dispensed by someone other than the investigator and therefore investigators were blinded to treatment assignment. Treatments were applied to ache sites on a dry face daily, 1 hour before bedtime, for 12 weeks. If necessary, the test material was also applied to other acne sites such as the shoulders, chest, or back. The subjects enrolled in this study were of both sexes, were 12 to 30 years old and lead mild to moderate acne (1 to 5 on Burke and Cunliffe' s scale), 11 with a minimum of 20 comedones and 10 facial inflammatory lesions. Patients with secondary or severe acne were not included. Patients who had been treated for acne with systemic retinoids during a 6-month period before the initiation of the study, or by systemic antibiotics (except penicillha), systemic or topical anfiinflammatories during the preceding 4 weeks, or by a topical treatment during the preceding 2 weeks were also excluded. The study was conducted from November 1988 through May 1989, following guidelines in accordance with the Helsinki Statement and approved by the Ethical Committee of the Montpellier-Ntmes C.H.U. All patients (as well as their parents or guardians, if they were minors) signed informed consent guidelines written in the respective language of each center after detailed explanation of the guidelines. This study was performed according to the Good Clinical Practices and the Good Laboratory Practices in the centers of Montpelller, France (investigator: J. Meynadier) and Warsaw, Poland (investigator: S. Jablonska).
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Treatments The evaluated products were 0.1% adapalene gel or 0.03% adapalene aqueous gel and a 0.025% tretinoin gel (all-trans retinoic acid). All treatments were supplied in identical 30 gm tubes. The treatments were not given to the patients by the investigator, but by an assistant, and patients were asked not to talk about the product appearance with the investigator. The patients were authorized to use their usual hygiene products (except as~ingent and alcohol-containing products).
Efficacy evaluation At each follow-up visit (inclusion visit, and weeks 1, 2, 4, 8, and 12), noninflammatory and inflammatory lesions (open and closed comedones, papules, pustules, nodules, and cysts) were counted on the forehead, the right and left cheeks, and the chin. The main outcome of this study was a change in the acne lesion number. A global score of patient acne was also established by the investigator on a scale from 0 to 10 according to the Burke and Cunllffe method. 11 For this purpose, each investigator was supplied with characteristic photographs of the different acne severity scores.
Safety evaluation Facial cutaneous tolerance was evaluated before the first application of the treatment and at Weeks 1, 2, 4, 8, and 12. The features taken into account were erythema, cutaneous dryness, scaling, burning, and pruritus. The first three were evaluated by the investigator. Pruritus and burning were evaluated by the patients themselves at two levels: Chronic reaction persisting between the applications, and temporary reaction occurring only after application. All these features were evaluated on a scale graduated from 0 to 3, in which 0, 1, 2, and 3 corresponded to no sensation, light or hardly perceptible, moderate, and severe sensation, respectively. In the case of an abnormally severe erythema or irritation that might be caused by treatment and constitute a case of contact dermatitis, test patches containing the different components of the formula were provided. Unexpected medical events and concomitant treatments were also noted.
CONCURRENT CONTROLLED STUDIES Patients and methods Study II: Adapalene 0.1% versus tretinoin, U.S. multicenter controlled study This U.S. multicenter randomized, investigator-masked trial was designed to compare the efficacy and safety of adapalene gel 0.1% with tretinoin gel 0.025% in the treatment of acne vulgaris. The study was performed by the following main investigators: A. Shalita (Brooklyn, NY), J.S. Weiss (Atlanta, GA), D.K. Chalker (Augusta, GA), C.N. Ellis (Ann Arbor, MI), A. Greenspan (May-
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Fig. 1. Reduction of total number of lesions during 12 weeks of treatment with 0.03% adapalene gel (diamonds), 0.1% adapalene gel (squares), an 0.025% tretinoin gel (triangles). (Figure from the article "Etude comparative de l'efficacit6 et de la tolrrance de gels d' adapalene ~ 0,1 et 0,003M et d'un gel de trrtinoine ~ 0, 025% dans le traitement de l'acne." M. Alirezai, J. Meyndier, S. Jablonska, J. Czemielewsli, M. Verschoore. Ann Dermatol Venereol, 1996;123:165-70. Reproduced with authorization of the Editing Committee, Copyright Masson Paris.)
wood, NJ), H.I. Katz (Fridley, MN), I. Kantor (Great Neck, NY), L.E. Millikan (New Orleans, LA), T. Swinehart (Denver CO), L. Swinyer (Salt Lake City, LIT), and C. Whitmore CLynchbttrg, VA). Inclusion criteria were identical to Study I. Three huntired twenty-three patients, 12 to 30 years old with global grades 13[ and 1B acne vulgaris were enrolled (approximately 30 patients per study center). The methods for evaluating efficacy and safety were identical to Study I. Laboratory evaluations for standard clinical chemistries, hematology, and urinalysis were performed in two study centers before and after a 3 month treatment period.
Study HI: Adapalene 0.1% versus tretinoin, European rnulticenter controlled study The European study was performed according to a multicenter, randomized, parallel group, investigatormasked design and followed the same method as Study I. The study was conducted in accordance with the Declaration of Helsinki, and written informed consent in the local language for each study center was obtained from the patients (and from their parents or guardian in the case of minors) after the procedure had been fully explained. The investigations were performed in accordance with good clinical practice and good laboratory practice. The results presented in this report are drawn from patients studied in eight centers located in seven different countries, the principal investigators of which were: W.J. Cunliffe (Great Britain); C.E. Orfanos and H. Gollnick (Germany); R. Caputo and C. Rigoni (Italy); L. FrrstrOm
Fig. 2. Mean percentage reduction in total lesion counts during 12-week treatment period. (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
(Finland); M. Heenen and D. Parent (Belgium); Y. Privat, P. Berbis, and C. Dufo (France); B. Dreno (France); A. Robledo Aguilar and E. Lopez Bran (Spain).
Treatments Study H and Study IH For both studies the lreatment method was the same. The products evaluated were a 0.1% (w/w) adapalene aqueous gel and a marketed 0.025% (w/w) tretinoin gel. The two treatments were supplied in identical 45 gm tubes. Directions for appfication were the same for the two treatments. As the two gels were physically different in appearance, the treatments were dispensed by someone other than the investigator, usually the investigator's assistant.
Efficacy evaluation Study II and Study HI For both studies the method applied was the same as in Study I. Patients were evaluated five times during the study period for efficacy and safety: At baseline and at weeks 2, 4, 8, and 12. The last available evaluation (either at week 12, or earfier for patients who did not complete the study) is referred to as endpoint. At each visit, individual noninflammatory and inflammatory lesions (open and closed comedones, papules, pustules, and nodules) on the forehead, the right and left cheeks, and the chin were counted. A global evaluation of the patients' ache condition was also performed by the investigator using a severity scale ranging from 0 to 10. This rating was based on a comparison with a series of representative photographs following the Leeds technique developed by Burke and Cunliffe. 1° Safety evaluation Study lI and Study HI For both studies the method applied was the same as in Study I. Adverse reactions were evaluated at each visit (i.e., at baseline and at weeks 2, 4, 8, and 12). Facial skin
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Fig. 4. Mean percentage reduction in inflammatory lesion counts during 12-week treatment period. (From Shalita A, et al. J Am Acad Dermatol 1996;34:482,5).
Table I. Evolution of acne lesions (average number and percentage reduction) for tretinoin and adapalene gel Average number
Average number
Week 0
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safety evaluation was based on the assessment of erythema, dryness, scaling, burning, and pruritus. The first three were evaluated by the investigator. Pruritus and burning were evaluated by the patients themselves, in two ways: Either as a chronic, persistent response between applications of treatment, or as a transient response, immediately after application. All of these features were ranked on a scale ranging from 0 to 3 where 0, 1, 2, and 3 corresponded to none, mild or barely perceptible, moderate, and severe, respectively. Unexpected medical events and concomitant therapy were also recorded. Adapalene plasma levels were determined at the last visit in 32 patients treated on large skin areas. The analytical method used was a reverse phase high pressure liquid chromatography (HPLC).
RESULTS: STUDIES I, II, III 1) Study I: Dose range study results A total of 89 male and female patients were included in Study I; 45 in Montpellier and 44 in Warsaw. In total, 29 patients received 0.03% ada-
palene gel, 30 patients 0.1% adapalene gel, and 30 patients 0.025% tretinoin. During the study, eight dropouts occurred: three for ineffectiveness after 8 weeks of treatment, and five for reasons not related to treatment. A regular decrease in the number of acne lesions was observed during the study in the three comparative groups of patients (Fig. 1). A dose range effect was observed for the two concentrations of adapalene; 0.03% was the least effective on inflamed lesions (p < 0.01, week 12), total acne lesion counts (p < 0.01 week 12), and global acne score (p < 0.05 at week 8 a n d p < 0.01 at week 12) (Table I). The low concentration of adapalene 0.03% gel was less effective than tretinoin in reducing noninflamed lesions (p < 0.05 at week 4 and week 8). The percent of patients experiencing more than 50% reduction of total acne lesions was 76% in the adapalene 0.03% group, 90% in the adapalene 0.1% group and 93% in the tretinoin group. The three products induced skin irritation, al-
S130
Journal of the American Academy of Dermatology June 1997
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Fig. 7. Mean percentage of patients at each visit experiencing dryness graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
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Fig. 6. Mean percentage of patients at each visit having scaling graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5).
though there were significant differences (p < 0.05) in intensity in favor of adapalene for erythema, scaling~ and burning.
2) Study II: Adapalene 0.1% versus tretinoin multicenter controlled study (U.S. study) 12 Of the 323 patients enrolled, 288 (149 adapalene, 139 tretinoin) completed through week 12 while the remaining 35 discontinued. Of these, 25 patients discontinued for nonmedical reasons and 10 because of medical events: four were in the adapalene gel group (two cases of acne flare, two cases of skin irritation) and six in the trefinoin gel group (one case of acne flare, one case of skin irritation, two cases of skin dryness, one case of herpes zoster, and one case
Visits
Fig. 8. Mean percentage of patients at each visit experiencing burning graded at least as mild (grade 1). (From Shalita A, et al. J Am Acad Dermatol 1996;34:482-5.)
of skin infection). In total, 323 patients were evaluable for safety and 290 for efficacy. The mean baseline lesion counts were not significantly different between the treatment groups (82.1 and 85.3 total lesions in adapalene and tretinoin group, respectively). Adapalene gel produced greater reductions in noninflammatory, inflammatory, and total lesion counts than tretinoin gel at week 12. The mean percent reduction in these types of lesions was as follows: 49% versus 37% for total lesions (p < 0.01), 46% versus 33% for noninflammatory (p=0.02), 48% versus 38% for inflammatory (p = 0.06) (Figs. 2 through 4). The number of patients treated with adapalene gel who experienced excellent improvement at week 12 was significantly greater (p < 0.05) for noninflammatory lesions (31%
Journal of the American Academy of Dermatology Volume 36, Number 6, Part 2
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vs 18%) and total lesions (29% vs 18%), but not for inflamrnatory lesions (32% vs 22%). The local irritation experienced, especially dnring the early stages of treatment, was typical of topical retinoid therapy. Irritation was, in general, mild for both treatments. There were significantly fewer (p < 0.05) incidents and a lesser degree of erythema, scaling, dryness, and burning throughout the study in the adapalene gel group (Figs 5 through 8).
Laboratory evaluations were performed in 54 patients before and after 3 months of treatment. No clinically significant changes were observed.
3) Study III: Adapalene 0.1% versus tretinoin multicenter controlled study (European study) A total of 268 patients were enrolled into the study, with 134 assigned to receive treatment with adapalene gel (74 males and 60 females, mean age 19.7 years, range 12 to 30 years) and 134 to tretinoin gel (69 males and 65 females, mean age 19.2 years, range 12 to 28 years). There were no significant differences between treatment groups in the study population with regard to age, sex, and skin complexion. A total of 32 patients did not complete the study. Eight of them (three in the adapalene group and five in the tretinoin group), were lost to follow-up or dis-
S132
Journal of the AmericanAcademyof Dermatology June 1997
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Fig. 15. Acne patient treated by adapalene 0.1% gel (after treatment), Study lB.
Fig. 14. Acne patient treated by adapalene 0.1% gel (before treatment), Study lB. continued for noncompliance with the protocol after the first visit (week 0). One patient in the tretinoin group was discontinued after the week 2 visit. The other 23 patients (10 in the adapalene group and 13
in the tretinoin group) were considered evaluable for efficacy because their treatment discontinuation took place after the week 4 visit. Therefore, of the 268 enrolled patients, 259 were deemed evaluable for efficacy (131 in the adapalene group and 128 in the tretinoin group), and 236 completed the 12 week study (121 in the adapalene group and 115 in the tretinoin group), In the two treatment groups, a regular decrease in acne lesion counts was observed as a function of time for all four features, with a maximum change close to 60% at week 12. One patient treated with adapalene was completely clear of lesions at week 8. No statistically significant differences between treatments were associated with any of these features at any of the evaluation points. Mean inflammatory and noninflammatory lesion counts also tended to decrease more rapidly in the adapalene-treated group than in the tretinoin-treated group at week 2 (Figs. 9 and 10). When patient groups were compared
Journal of the AmericanAcademyof Dermatology Volume 36, Number 6, Part 2
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Fig. 16. Acne patient treated by adapalene 0.1% gel (before treatment), Study lB.
Fig. 17. Acne patient treated by adapalene 0.1% gel (after treatment), Study 11I.
according to their degree of reduction in each feature relative to baseline, the percentage of patients who experienced a more than 50% decrease in total lesion counts at week 12 was 72% in the adapalene group and 75% in the tretinoin group. Seven patients were discontinued from therapy because of treatment failure. Two were in the adapalene group and five in the tretinoin group. At baseline, the scores of all features taken into account for evaluating safety were similar between treatments. At each subsequent time point, the mean scores for all of the tolerance features, except persistent pruritus, were slightly higher than baseline in both treatment groups, increasing to a maximal value at week 2, and then steadily decreasing. When adapalene and tretinoin gels were compared, significantly lower mean scores (p < 0.05) were obtained with adapalene for the following features: burning after application (weeks 2 to 12, p < 0.01), persistent burning (week 8), pruritus after application (week
12), and dryness and scaling (weeks 8 and 12) (Figs 11 through 13). Mean erythema scores were not significantly different between treatments. Dosage regimen alterations for skin safety reasons were required in 19 patients treated with adapalene gel and in 29 patients treated with tretinoin gel. DISCUSSION
The efficacy of tretinoin for the treatment of acne vulgaris has been demonstrated in several studies comparing 0.1%, 0.05 %, and 0.025 % concentrations in various vehicles to the vehicle aloneJ 3 To determine the efficacy of adapalene gel, the highest commercially available strength of tretinoin gel was chosen. For this reason, adapalene gel 0.1% was compared with tretinoin gel 0.025% in two large multicenter trials. After a 12-week treatment of patients with mild to moderate acne vulgaris (grades 1 to 5 global facial acne score), adapalene 0.1% gel proved to be as ef-
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Cunliffe et al.
fective as tretinoin 0.025% gel in one study and significantly more effective than tretinoin gel in another. Clinical results of adapalene treatment are shown in Figs. 14 through 17. No systemic effects were observed with either of the tested products. Adapalene 0.1% gel induced mild skin irritation, increasing in intensity to a maximum at week 2 of treatment before regularly decreasing to week 12. The irritation intensity with adapalene 0.1% gel was significantly lower than with tretinoin gel for the following: Burning after application, persistent buming, pruritus after application, dryness, and scaling. No patients treated with adapalene gel discontinued therapy because of side effects, as opposed to four patients receiving tretinoin gel (all with an erythematous eruption). Fewer patients receiving adapalene (19 vs 29) altered the dosage for safety reasons. We conclude that topical 0.1% adapalene gel is an effective, safe and well-tolerated treatment for acne vulgaris, resulting in low systemic exposure and no detectable systemic toxicity. It is as effective as topical tretinoin and has a superior skin safety profile. REFERENCES 1. Bernard BA. Adapalene, a new chemical entity with retinoid activity. Skin Pharmacol 1993;6Supp. L:61-9. 2. Elbaum DJ. Comparison of the stability of topical isotretinoin and topical tretinoin and their efficacy in acne. J Am Acad Dermatol 1988;19:486-91. 3. Asselineau D, Cavey MT, Shroot B, et al. Control of epi-
4.
5.
6. 7.
8. 9.
10.
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13,
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