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Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac®) and a proprietary 0.025% tretinoin gel formulation (Aberela®) in the topical control of facial acne
Journal of the European Academy of Dermatology and Venereology 11 (1998) 227–233
Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne J.R. Richter a ,*, L.R. Fo¨rstro¨m b, U.O. Kiistala c, E.G. Jung d a
Yamanouchi Europe B.V., Medical Department Europe, Elisabethhof 19, P.O. Box 108, 2350 AC Leiderdorp, The Netherlands b Keskuskadun Laakarikeskus, Keskuskatu 6, 00250 Helsinki, Finland c Central Military Hospital, Mannerheimintie 164, PL 50, 00301 Helsinki, Finland d Klinikum der Stadt Mannheim Hautklinik, P.O. Box 100023, 68135 Mannheim 1, Germany
Abstract Background A formulation containing agents affecting the non-inflammatory as well as the inflammatory lesions of acne vulgaris at the same time would be efficient, probably showing a high efficacy and possibly a considerable shortening of the duration of treatment. One single formulation would simplify drug administration thereby enhancing patient compliance and possibly leading to improved therapeutic results. In two studies this seems to have been corroborated for the fixed clindamycin phosphate-tretinoin gel formulation. Objective This study was designed to assess whether the recently developed fixed formulation of 1.2% clindamycin phosphate and 0.025% tretinoin in a gel base (Velac), further referred to as Clindamycin phosphate Tretinoin Gel is at least as effective as a proprietary 0.025% tretinoin gel formulation (Aberela, Janssen Cilag Ab, Sollentuna, Sweden; further defined as tretinoin) showing an additional anti-inflammatory effect in the treatment of moderate to severe acne vulgaris. Methods In a double-blind, randomised study 72 patients were treated with CTG and 73 with tretinoin gel in a once daily regimen for 12 weeks. Responses, irritation as well as possible systemic and other adverse effects were recorded after 4, 8 and 12 weeks of treatment and the improvement, compared to baseline, assessed in all included patients. An additional assessment of the safety parameters was carried out at week 2. Parameters of efficacy were the various acne lesion counts, the overall acne severity grade and the calculated totals of acne lesion counts. Results CTG was statistically significantly more effective than tretinoin at the P = 0.05 level in the papular and the total mean inflammatory lesion counts as well as in the estimated or calculated mean overall acne severity scores. CTG and tretinoin gel were equally effective in the remaining parameters: open and closed comedones, the calculated total mean comedone, the pustule as well as the nodule lesion counts. The onset of action was faster for CTG than for tretinoin gel and evident in all assessed parameters except in open comedone lesion counts. In the calculated total mean acne lesion counts, half of all acne lesions had disappeared by week 6 of treatment with CTG, whereas this was recorded at week 9 for tretinoin gel. No clinically relevant changes in the parameters of safety as a consequence of treatment were observed, although the burning component of irritation was shown to be significantly less for CTG than for tretinoin gel. The observed adverse effects were considered minor. Treatment had to be discontinued in five patients on CTG and three on tretinoin. Conclusion The addition of clindamycin to tretinoin, as in CTG, enhances the comedolytic efficacy of tretinoin in moderate to severe acne of the face, maintaining at the same time its anti-inflammatory efficacy thus accelerating resolution of all types of acne lesions without affecting the safety of response to both components. 1998 Elsevier Science B.V. All rights reserved * Corresponding author. Tel.: +31 71 5455706; fax: +31 71 5455223.
0926-9959/98/$ - see front matter PII S0926-9959 (98 )0 0071-3
1998 Elsevier Science B.V. All rights reserved
228
J.R. Richter et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 227–233
Keywords: Aberela; Acne vulgaris; Clindamycin; Clinical trials; Cutaneous administration; Double-blind method; Drug combinations; Tretinoin; Velac gel
1. Introduction The fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation referred to as CTG was developed recently for the topical treatment of acne. Both active constituents of CTG have been used topically for decades and are specifically active in either the non-inflammatory or inflammatory lesions of acne. In the usually strictly defined assessment periods of 12 weeks maximum, both show about the same 60–80% mean reduction of baseline lesion counts. In the annals of topica1 acne treatment the idea of using each preparations’ specific properties to obtain a broad spectrum of activity was carried out using either topical 0.025% tretinoin and 2% erythromycin [1] or 0.025% topical tretinoin and 1% clindamycin phosphate [2]. Possibly because of pharmaceutical incompatibility of these agents at the time, it was more a question of combined treatment, administering the preparations sequentially with their own appropriate dosage schemes, rather than the use of a fixed combination product with its own established dosage regimen as in CTG. Not long after the report of sequential treatment of acne with 0.025% topical tretinoin and 2% erythromycin, results of acne treatment with fixed 0.025% tretinoin, 4% erythromyocin base formulations were described [3,4]. This latter preparation is reported to be available and in use today [5–7]. Apparently the therapeutic attractiveness of this particular type of preparation also invites new developments, because recently the efficacy of a fixed combination of 0.025% tretinoin and 2.7% erythromycin lauryl sulphate solution in acne has been tested and reported [8]. Unlike the progress in development of tretinoin-erythromycin formulations, that of the tretinoin-clindamycin combinations has remained static in the state of sequential tretinoin-clindamycin treatment [2]. Today, this has been redressed by the compounding of a fixed 0.025% tretinoin, 1.2% clindamycin phosphate formulation referred to as CTG. This specific combination is considered to have clinical effects surpassing those of the individual components alone
when all acne lesion types are considered [9]. In addition, it was thought that CTG could shorten the duration of treatment and would be better tolerated since the irritant effects of tretinoin might be moderated by the presence of clindamycin, as evidenced in a study of similar design [2]. The single mode of administration, as well as the decreased possibility of irritant effects, would improve patient compliance to treatment. This study intends to determine whether or not efficacy and safety of CTG in moderate to severe acne of the face produces similar results in a comparison with a proprietary tretinoin preparation.
2. Patients and methods The design and implementation of this present study were identical to those of an earlier similar study which compared the efficacy of CTG with that of tretinoin extemporaneously compounded in the Velac (Yamanouchi Europe BV, Leiderdorp, The Netherlands) gel formulation base [9]. A total of 161 out-patients from dermatological clinics were selected for this study. They had to comply with inclusion criteria mainly related to age range (14–26 years) and acne severity grades of 3 and higher according to the modified scoring scale of Cook [10]. Exclusion criteria included specifically: (1) use of tretinoin, topical or systemic antibiotics, irritants or hormonal treatments in the 4 weeks preceding the study; (2) skin disorders likely to affect drug absorption or disorders requiring medical treatment within 5 days before the start of the study; (3) known or suspected hypersensitivity to the agents in CTG or related compounds; (4) history of serious allergic reactions to drug treatment; (5) pregnancy, lactation and/or use of oral contraceptives with a specific anti-androgenic action or any oral contraceptive treatment initiated within 3 months before or during the study. The approval of the Ethics Committees was obtained for each study centre separately. Suitable
J.R. Richter et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 227–233
patients were informed concerning the purpose and possible consequences of the study according to the Informed Consent Guidelines and included in the study after signing their consent or after obtaining the signed Witnessed Oral Consent. The total number of 161 patients selected for this study was determined by the requirement that at least 60 assessable patients in each group had to remain to show a 20% difference in percentage reduction of inflammatory lesions after 12 weeks of treatment. This was based on the chosen significance and power levels of a = 0.05 (two sided) and 1 − b = 0.80. In a double-blind, bi-national (Finland, Germany), multi-centre (2× Helsinki; 1× Mannheim) set-up, 80 of 161 patients with moderate to severe acne of the face were randomly assigned to treatment with CTG. The remaining 81 patients received tretinoin with the same once daily dosage regime. All acne lesions of the face, i.e. open and closed comedones, papules, pustules and nodules were counted and the overall acne severity graded at the start and after 4, 8 and 12 weeks of treatment. Similar mean acne lesion counts were then added together at the various assessment times to form the calculated total mean number of comedone lesion counts, the calculated total mean number of inflammatory acne lesion count and the calculated overall acne severity grade, which is the sum of the total mean number of comedone lesion counts and the total mean number of inflammatory lesion counts. Efficacy of both treatment modalities was assessed from the obtained improvements of each parameter at the agreed times of assessment. The efficacy of the clindamycin contribution to the comedolytic efficacy of tretinoin in CTG could be deduced from the differences in efficacy of CTG and tretinoin on the various inflammatory parameters. Whether the addition of the antibiotic to tretinoin in CTG impairs the comedolytic effect of tretinoin could at the same time be deduced from comparisons of the results obtained with both comparative preparations in the non-inflammatory forms of acne, leaving differences of possible vehicle contribution aside. The safety of the instituted treatment modalities was analysed on the basis of the results of assessments of incidence and severity of the symptoms of irritation (erythema, burning, pruritus, scaling and induration)
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graded and recorded by the investigator at week 2, 4, 8 and 12 of treatment using a 5-point severity scale (0 = none to 4 = very severe). All 161 included patients were subjected to this particular safety assessment. Other safety parameters assessed were the reported type, number and severity of adverse events during treatment. Possible changes in blood chemistry and hematological data at the end of treatment and those changes observed in general circulatory (heart rate, systolic and diastolic blood pressure) or physical diagnosis (head and neck, heart, lungs, abdomen, reflexes) were compared to baseline recordings to assess the systemic safety of both preparations. Both preparations had to be administered in once-daily regimen on both sides of the face at bedtime, and the duration of the total treatment period was 12 weeks. Unused medication was collected after the last assessment. 2.1. Statistical analysis Data produced by patients who took an incomplete course of treatment, notably less than 10 weeks, missed more than 24 applications or more than eight applications between weeks 8 and 12 of treatment, were excluded from statistical analysis. The collected and adjusted, sifted data were subjected to analysis using the two sample t-test at the a = 0.05 significance level to determine whether the observed differences in the two treatment modalities would be chance happenings. For the calculated total mean number of comedone lesion counts, the calculated total mean number of inflammatory lesion counts and the total mean number of all acne lesion counts, representing the calculated overall acne severity grade, the Wilcoxon test was used. The assessment results of laboratory data and vital signs as a result of treatment with CTG or tretinoin were subjected to graphic analysis. Differences in the degree of local irritation between treatments were analysed using the Mantel–Haensel Chi-squared test.
3. Results Of 81 acne patients randomly assigned to treatment with CTG, 75 were included for assessment. The original tretinoin group comprised 80 subjects whom 77
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Table 1
Table 2
Demographic characteristics of the global and strictly defined (in italics) CTG and tretinoin study populations
The calculated 50% improvement level of mean baseline comedone lesion counts during treatment
Preparation
CTG Tretinoin Total
No. of patients
75 69 77 69 152 138
Sex
Age
Male Female
Mean ± SD Range (years) (years)
47 44 41 39 88 83
19.9 19.9 19.5 19.6 19.7 19.7
28 25 36 30 64 55
50% improvement level (weeks)
± ± ± ± ± ±
2.8 2.7 3.0 3.0 2.9 2.9
14–26 14–25 14–26 14–26 14–26 14–26
remained for final assessment. Sex distribution and age ranges of this global, intention-to-treat study population are presented in Table 1. Excluding those patients who did not report for assessments at the agreed points of time (CTG, three and tretinoin, four patients) and those showing protocol infringements or dropouts because of adverse effects, a strictly protocol defined study population of 69 patients on CTG and 69 patients on tretinoin remained (see Table 1). The presented data, however refers to the intention-to-treat population of 152 patients of whom 75 were assigned to treatment with CTG and 77 to treatment with tretinoin. 3.1. Assessment of efficacy CTG and tretinoin were shown to have a similar efficacy in the reduction of open and closed comedones (see Fig. 1). At the end of the 12 week treatment
Fig. 1. Improvement of the mean number of open (-A-), closed (-B-) and the calculated total mean number of comedone lesion counts (-♦-) after treatment with CTG (–) and tretinoin (-.-.-.).
Mean lesion counts
CTG
Tretinoin
Open comedones Closed comedones Total comedones
9 7 6
9 9 9
period a 58% reduction of open comedone lesion counts with regard to baseline was obtained with CTG compared to 53% with tretinoin. The difference with a confidence interval (CI) of −4.84 to 14.98 was statistically not significant at the 5% level (P = 0.3). In closed comedones the efficacy of CTG was numerically higher than that of tretinoin in week 12 of treatment; the difference between the obtained improvements of 65% for CTG and 52% for tretinoin were, however, statistically not significant at the P = 0.06 level (95% CI: −0.76 to 22.68). Twelve weeks of treatment with CTG induced a mean reduction of 61% of the calculated total mean number of comedone lesion counts and 55% with tretinoin in the same period of treatment (see Fig. 1). No statistically significant difference could be calculated for these results (P = 0.15, 95% CI: −1.59 to 14.80). Response to treatment as reflected by the 50% lesion reduction of comedone baseline levels, was faster for CTG than for tretinoin in closed (20%) and calculated mean number of comedones (30%) and appeared to be equal in open comedones (Table 2). The effect of CTG or tretinoin on the lesion count of the inflammatory forms of acne, i.e. papules, pustules and nodules, after 4, 8 or 12 weeks of treatment are presented in Fig. 2. In the reduction of papules CTG appeared to be significantly more effective than tretinoin at the P , 0.05 level at all three points of assessment: after 4 weeks, P = 0.04; after 8 weeks, P = 0.01; after 12 weeks, P = 0.0004; 95% CI: 10.74 to 34.20. No statistical differences in efficacy between the two preparations was observed in pustules or nodules at the end of 4, 8 or 12 weeks of treatment. When the speed of efficacy as a function of the duration of treatment was assessed CTG was much more effective than tretinoin in papules and pustules and similar in efficacy in nodules. A 50% improve-
J.R. Richter et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 227–233
Fig. 2. Improvement of the mean number of papules (-♦-), pustules (-B-), nodules (-X-) and the calculated total mean number of inflammatory acne lesion counts (-W-) after treatment with CTG (–) and tretinoin (-.-.-).
ment of mean baseline papular or pustular lesion counts was achieved in a shorter time with CTG than with tretinoin (Table 3). When the difference of both treatment modalities on the calculated mean total of inflammatory acne lesion counts was examined, the efficacy at weeks 4 and 8, and at the end of treatment was statistically significant (P = 0.04, or P = 0.01, and highly significantly (P = 0.006; 95% CI: −8.22 to 28.75) in favour of CTG (see Fig. 2). Compared to baseline scores, a mean improvement of about 73% was obtained with CTG compared to about 54% with tretinoin at week 12 of treatment. The 50% reduction rate of the calculated mean total of inflammatory lesions with CTG was obtained with a 60% shorter duration of treatment than with tretinoin (Table 3). When changes in the global, overall acne severity grade, i.e. estimated by the investigator, were recorded as a function of the duration of treatment (see Fig. 3), CTG was reported to induce an improvement of 49% after 12 weeks of treatment compared to baseline, while this improvement was only 39% for Table 3 The calculated 50% improvement level of mean baseline inflammatory lesion counts during treatment 50% improvement level (weeks) Mean lesion counts
CTG
Tretinoin
Papules Pustules Nodules Total inflammatory lesions
5.5 3.5 4 5
8.5 7.5 4 8
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Fig. 3. Percent improvement of the global (-A-) or the calculated overall acne severity grade after (-B-) treatment with CTG (–) and tretinoin (-.-.-.).
tretinoin. The observed difference was statistically significant at the P = 0.02 level, with a 95% confidence interval of 8.22 to 28.75. A significant difference in efficacy between the two treatment modalities in this parameter was also observed at week 8 of treatment (P = 0.014). A response of the global, overall acne severity grade to treatment showing a 50% reduction of baseline recordings was obtained with CTG in week 12 and much slower with tretinoin, calculated to be 2 weeks after the end of treatment. If all recordings of non-inflammatory and inflammatory lesion counts at the four assessment times are put together we will, as a matter of fact, have obtained the actual, calculated overall acne severity grade and its improvements as the result of treatment (see Fig. 3). The mean improvement of this parameter, in the CTG treated group amounted to 64%, compared to 54% for the tretinoin group. After 12 weeks this difference in efficacy was found to be significant P = 0.01 (with a 95% CI: 2.15 to 17.36 using the Wilcoxon test. The 50% reduction level of baseline calculated overall acne severity grade recordings with CTG was reached in week 6 and with tretinoin in week 9 of treatment. A summary of the results of efficacy assessments is presented in Table 4. 3.2. Assessment of safety Of 72 patients treated with CTG and of 73 patients treated with tretinoin who completed 12 weeks of treatment, five patients on CTG and three patients on tretinoin showed adverse effects requiring withdrawal from the study. Of the five withdrawn patients
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Table 4 Summary of the results of acne treatment with CTG and tretinoin Comparison of efficacy Non-inflammatory acne lesion types Open comedones Closed comedones Total comedones Inflammatory acne lesion types Papules Pustules, nodules Total inflammatory Global acne severity Calculated acne severity
No difference No difference No difference CTG better (P No difference CTG better (P CTG better (P CTG better (P
= 0.0004) = 0.006) = 0.02) = 0.01)
on CTG a burning sensation was reported by one, while two patients complained of burning in addition to concomitant inflammation. Another two patients reported irritation accompanied by exfoliation. All three patients on tretinoin who were withdrawn had to do so because of the severity of burning. The reported irritation and burning are the typical cutaneous side-effects of tretinoin; they disappear on discontinuation of treatment. Other adverse effects spontaneously reported by patients during treatment concerned dryness of the skin; this was reported by three patients treated with CTG and one patient on tretinoin. None of the four assessed symptoms of irritation, specifically erythma, induration, scaling and pruritus graded according to the degree of severity from none (0) to very severe (4) showed remarkable or statistically significant changes in either the CTG or tretinoin group. Severity was highest in week 2 of treatment improving steadily until the last week. Erythema and scaling could, however, still be observed in a number of patients at the end of treatment. Severe forms of erythema were present in five patients on CTG and seven on tretinoin, while scaling of the same severity was observed in one patient on CTG and in three on tretinoin. In the 5th assessed symptom of irritation, notably burning, however, treatment with CTG showed statistically significantly less burning than treatment with tretinoin at all weeks of assessment. In the last week of CTG treatment no burning was reported in 61 patients, mild burning in 10 and moderate to severe burning in one patient. For tretinoin, the results were 42, 25 and 6, respectively. Assessment of the general safety parameters, such
as heart rate, blood pressure or physical examination carried out in all 161 patients showed no clinically relevant changes after 12 weeks of treatment in either the CTG or the tretinoin group. Other general safety parameters such as the complete total and differential blood cell count as well as hepatic and renal function tests carried out in 40 CTG and 40 tretinoin treated patients of one centre, likewise showed no clinical relevant changes at the end of treatment.
4. Discussion Considering the similar efficacy of both preparations in open comedones, 58% for CTG against 53% for tretinoin, and the numerically better effect (P = 0.06) of CTG compared to tretinoin in closed comedones, i.e. 63% for CTG compared to 52% for tretinoin, the addition of clindamycin to tretinoin in CTG apparently tends to improve the comedolytic efficacy of tretinoin itself, assuming the vehicle effects to be equal. This assumption is indicated also by the finding that the 50% reduction levels of the calculated total mean number of comedone lesion counts was week 6 for CTG and week 9 for tretinoin. As could be expected from the easy penetrability of open comedones the 50% reduction level of these lesions was roughly reached in the same week 9 of treatment. In closed comedones the increased numbers of anaerobic P. acnes requires the presence of an antibiotic for rapid efficacy. The clindamycin component of CTG appears to have contributed substantially to the improvement in these type of acne lesions, although a possible increased efficiency of the active agents by this particular formulation base cannot be ruled out entirely. In fact the 50% improvement level was obtained at week 7 with CTG compared to week 9 with tretinoin. The percent reduction of 61% for CTG in the total of non-inflammatory lesions of acne demonstrates that the clindamycin addition to tretinoin, as in CTG, does at the same time apparently not affect the efficacy of tretinoin as can be deduced from the 55% tretinoin efficacy in this parameter. The anti-inflammatory and antibacterial activity of clindamycin added to that of the comedolytic efficacy of tretinoin is supposed to be most useful in the treatment of inflammatory forms of acne. This was confirmed by the reported significant differences in efficacy
J.R. Richter et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 227–233
between CTG and tretinoin. As was observed, the mean papule reductions from baseline are statistically significantly different at weeks 4, 8 and 12 of assessment. Similar significant difference in efficacy between the two treatment modalities were observed in the calculated total mean number of inflammatory lesion. Considerable differences were also observed in the 50% improvement levels which was about 5.5 weeks for CTG compared to 8.5 weeks for tretinoin in papules and 5 weeks compared to 8 weeks in the calculated total of inflammatory lesions, respectively (Table 4). Why no statistically significant differences in efficacy of the two treatment modalities in pustules and nodules could be demonstrated in this study may have been due to the low number of patients showing sufficiently assessable lesion counts. Those patients with less than 10 lesions at baseline were excluded from statistical analysis. However, the calculated, overall severity score of acne lesions was shown to be closely correlated with the proposed acne severity score of this study notably grade 3 or higher (Pearson correlation 0.60 to 0.78). This means that efficacy assessments of CTG or tretinoin in these ‘deficient’ parameters can possibly only be carried out properly by selecting patients presenting maximal numbers of pustules and nodules or choosing the highest mentioned Cook grades, i.e. classes 6–8 of acne severity. Significant differences in efficacy between the two treatments was also evident from the global as well as from the calculated overall acne severity grades at the various times of assessment. In both parameters, the 50% improvement level was reached several weeks earlier with CTG than with tretinoin. In the estimated, overall acne severity grade this amounted to 2 weeks, whereas in the calculated overall acne severity grade this appeared to be 3 weeks, establishing the rapid onset of action of CTG for this parameter. From the results of the safety assessments it could be deduced that the addition of clindamycin to tretinoin like in the Velac gel formulation, apparently significantly inhibits the burning inherent in treatment with tretinoin alone. A similar experience was reported for the sequential use of tretinoin and clindamycin phosphate years ago [2]. It should also be remembered that an emollient effect of the formulation base could have contributed to such differences in tolerability. This was, however, not clearly evident from the spontaneously reported incidences of burn-
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ing and irritation in five patients on CTG and three on tretinoin. Although the results of the above mentioned safety assessment and the incidence of spontaneously reported adverse effects in the clinical studies might indeed confirm the alleviating influence of clindamycin on tretinoin in the CTG composition, a definite conclusion must be postponed until more clinical experience with CTG is available.
Acknowledgements The authors wish to thank Dr. P. Talsma, Yamanouchi Europe BV, The Netherlands for his statistical calculations.
References [1] Mills OH, Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Derm Venereol (Stockh) 1978;58:555–557. [2] Rietschel RL, Duncan SH. Clindamycin phosphate used in combination with tretinoin in the treatment of acne. Int J Dermatol 1983;22:41–43. [3] Aron-Brunetiere R, Hewitt J, Puisant A, et al. Etude comparative a double insu de deux traitements locaux de l’acne: la tretinoine et l’association tretinoine erythromycine base. Gaz Med France 1980;87:3635–3638. [4] Amblard P, Bazex A, Beylot C, et al. L’association tretinoine-erythromycine base. Nouveau traitement local de l’acne. Etude multicentrique sur 347 cas. Sem Hop Paris 1980;56:911–915. [5] Korting HC, Braun-Falco O. Efficacy and tolerability of combined topical treatment of acne vulgaris with tretinoin and erythromycin in general practice. Drugs Exp Clin Res 1989;15(9):447–451. [6] Kossmann J. Simultaneous local treatment of acne vulgaris with tretinoin and erythromycin: results of an open multicentre trial. Aktuelle Dermatologie 1989;15:258–260. [7] Pfannschmidt N, Bauer R, Kreysel HW. Combined treatment of acne vulgaris with topical erythromycin and tretinoin. Z Hautkr 1988;63:366–368. [8] Fonseca E, Ferrandiz C, Camarasa JG, et al. Erythromycin lauryl sulphate in combination with tretinoin in the topical treatment of acne vulgaris. A multi-centre, double-blind clinical trial. J Dermatol Treat 1995;6:47–50. [9] Richter JR, Bonsema MT, De Boulle KLVM, et al. Efficacy of a fixed clindamycin phosphate 1.2% tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions. J Dermatol Treat 1998;9:81–90. [10] Allen BS, Graham Smith J. Various parameters for grading acne vulgaris. Arch Dermatol 1982;11:23–25.
Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne J.R. Richter a ,*, L.R. Fo¨rstro¨m b, U.O. Kiistala c, E.G. Jung d a
Yamanouchi Europe B.V., Medical Department Europe, Elisabethhof 19, P.O. Box 108, 2350 AC Leiderdorp, The Netherlands b Keskuskadun Laakarikeskus, Keskuskatu 6, 00250 Helsinki, Finland c Central Military Hospital, Mannerheimintie 164, PL 50, 00301 Helsinki, Finland d Klinikum der Stadt Mannheim Hautklinik, P.O. Box 100023, 68135 Mannheim 1, Germany
Abstract Background A formulation containing agents affecting the non-inflammatory as well as the inflammatory lesions of acne vulgaris at the same time would be efficient, probably showing a high efficacy and possibly a considerable shortening of the duration of treatment. One single formulation would simplify drug administration thereby enhancing patient compliance and possibly leading to improved therapeutic results. In two studies this seems to have been corroborated for the fixed clindamycin phosphate-tretinoin gel formulation. Objective This study was designed to assess whether the recently developed fixed formulation of 1.2% clindamycin phosphate and 0.025% tretinoin in a gel base (Velac), further referred to as Clindamycin phosphate Tretinoin Gel is at least as effective as a proprietary 0.025% tretinoin gel formulation (Aberela, Janssen Cilag Ab, Sollentuna, Sweden; further defined as tretinoin) showing an additional anti-inflammatory effect in the treatment of moderate to severe acne vulgaris. Methods In a double-blind, randomised study 72 patients were treated with CTG and 73 with tretinoin gel in a once daily regimen for 12 weeks. Responses, irritation as well as possible systemic and other adverse effects were recorded after 4, 8 and 12 weeks of treatment and the improvement, compared to baseline, assessed in all included patients. An additional assessment of the safety parameters was carried out at week 2. Parameters of efficacy were the various acne lesion counts, the overall acne severity grade and the calculated totals of acne lesion counts. Results CTG was statistically significantly more effective than tretinoin at the P = 0.05 level in the papular and the total mean inflammatory lesion counts as well as in the estimated or calculated mean overall acne severity scores. CTG and tretinoin gel were equally effective in the remaining parameters: open and closed comedones, the calculated total mean comedone, the pustule as well as the nodule lesion counts. The onset of action was faster for CTG than for tretinoin gel and evident in all assessed parameters except in open comedone lesion counts. In the calculated total mean acne lesion counts, half of all acne lesions had disappeared by week 6 of treatment with CTG, whereas this was recorded at week 9 for tretinoin gel. No clinically relevant changes in the parameters of safety as a consequence of treatment were observed, although the burning component of irritation was shown to be significantly less for CTG than for tretinoin gel. The observed adverse effects were considered minor. Treatment had to be discontinued in five patients on CTG and three on tretinoin. Conclusion The addition of clindamycin to tretinoin, as in CTG, enhances the comedolytic efficacy of tretinoin in moderate to severe acne of the face, maintaining at the same time its anti-inflammatory efficacy thus accelerating resolution of all types of acne lesions without affecting the safety of response to both components. 1998 Elsevier Science B.V. All rights reserved * Corresponding author. Tel.: +31 71 5455706; fax: +31 71 5455223.
0926-9959/98/$ - see front matter PII S0926-9959 (98 )0 0071-3
1998 Elsevier Science B.V. All rights reserved
228
J.R. Richter et al. / J. Eur. Acad. Dermatol. Venereol. 11 (1998) 227–233
Keywords: Aberela; Acne vulgaris; Clindamycin; Clinical trials; Cutaneous administration; Double-blind method; Drug combinations; Tretinoin; Velac gel
1. Introduction The fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation referred to as CTG was developed recently for the topical treatment of acne. Both active constituents of CTG have been used topically for decades and are specifically active in either the non-inflammatory or inflammatory lesions of acne. In the usually strictly defined assessment periods of 12 weeks maximum, both show about the same 60–80% mean reduction of baseline lesion counts. In the annals of topica1 acne treatment the idea of using each preparations’ specific properties to obtain a broad spectrum of activity was carried out using either topical 0.025% tretinoin and 2% erythromycin [1] or 0.025% topical tretinoin and 1% clindamycin phosphate [2]. Possibly because of pharmaceutical incompatibility of these agents at the time, it was more a question of combined treatment, administering the preparations sequentially with their own appropriate dosage schemes, rather than the use of a fixed combination product with its own established dosage regimen as in CTG. Not long after the report of sequential treatment of acne with 0.025% topical tretinoin and 2% erythromycin, results of acne treatment with fixed 0.025% tretinoin, 4% erythromyocin base formulations were described [3,4]. This latter preparation is reported to be available and in use today [5–7]. Apparently the therapeutic attractiveness of this particular type of preparation also invites new developments, because recently the efficacy of a fixed combination of 0.025% tretinoin and 2.7% erythromycin lauryl sulphate solution in acne has been tested and reported [8]. Unlike the progress in development of tretinoin-erythromycin formulations, that of the tretinoin-clindamycin combinations has remained static in the state of sequential tretinoin-clindamycin treatment [2]. Today, this has been redressed by the compounding of a fixed 0.025% tretinoin, 1.2% clindamycin phosphate formulation referred to as CTG. This specific combination is considered to have clinical effects surpassing those of the individual components alone
when all acne lesion types are considered [9]. In addition, it was thought that CTG could shorten the duration of treatment and would be better tolerated since the irritant effects of tretinoin might be moderated by the presence of clindamycin, as evidenced in a study of similar design [2]. The single mode of administration, as well as the decreased possibility of irritant effects, would improve patient compliance to treatment. This study intends to determine whether or not efficacy and safety of CTG in moderate to severe acne of the face produces similar results in a comparison with a proprietary tretinoin preparation.
2. Patients and methods The design and implementation of this present study were identical to those of an earlier similar study which compared the efficacy of CTG with that of tretinoin extemporaneously compounded in the Velac (Yamanouchi Europe BV, Leiderdorp, The Netherlands) gel formulation base [9]. A total of 161 out-patients from dermatological clinics were selected for this study. They had to comply with inclusion criteria mainly related to age range (14–26 years) and acne severity grades of 3 and higher according to the modified scoring scale of Cook [10]. Exclusion criteria included specifically: (1) use of tretinoin, topical or systemic antibiotics, irritants or hormonal treatments in the 4 weeks preceding the study; (2) skin disorders likely to affect drug absorption or disorders requiring medical treatment within 5 days before the start of the study; (3) known or suspected hypersensitivity to the agents in CTG or related compounds; (4) history of serious allergic reactions to drug treatment; (5) pregnancy, lactation and/or use of oral contraceptives with a specific anti-androgenic action or any oral contraceptive treatment initiated within 3 months before or during the study. The approval of the Ethics Committees was obtained for each study centre separately. Suitable
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patients were informed concerning the purpose and possible consequences of the study according to the Informed Consent Guidelines and included in the study after signing their consent or after obtaining the signed Witnessed Oral Consent. The total number of 161 patients selected for this study was determined by the requirement that at least 60 assessable patients in each group had to remain to show a 20% difference in percentage reduction of inflammatory lesions after 12 weeks of treatment. This was based on the chosen significance and power levels of a = 0.05 (two sided) and 1 − b = 0.80. In a double-blind, bi-national (Finland, Germany), multi-centre (2× Helsinki; 1× Mannheim) set-up, 80 of 161 patients with moderate to severe acne of the face were randomly assigned to treatment with CTG. The remaining 81 patients received tretinoin with the same once daily dosage regime. All acne lesions of the face, i.e. open and closed comedones, papules, pustules and nodules were counted and the overall acne severity graded at the start and after 4, 8 and 12 weeks of treatment. Similar mean acne lesion counts were then added together at the various assessment times to form the calculated total mean number of comedone lesion counts, the calculated total mean number of inflammatory acne lesion count and the calculated overall acne severity grade, which is the sum of the total mean number of comedone lesion counts and the total mean number of inflammatory lesion counts. Efficacy of both treatment modalities was assessed from the obtained improvements of each parameter at the agreed times of assessment. The efficacy of the clindamycin contribution to the comedolytic efficacy of tretinoin in CTG could be deduced from the differences in efficacy of CTG and tretinoin on the various inflammatory parameters. Whether the addition of the antibiotic to tretinoin in CTG impairs the comedolytic effect of tretinoin could at the same time be deduced from comparisons of the results obtained with both comparative preparations in the non-inflammatory forms of acne, leaving differences of possible vehicle contribution aside. The safety of the instituted treatment modalities was analysed on the basis of the results of assessments of incidence and severity of the symptoms of irritation (erythema, burning, pruritus, scaling and induration)
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graded and recorded by the investigator at week 2, 4, 8 and 12 of treatment using a 5-point severity scale (0 = none to 4 = very severe). All 161 included patients were subjected to this particular safety assessment. Other safety parameters assessed were the reported type, number and severity of adverse events during treatment. Possible changes in blood chemistry and hematological data at the end of treatment and those changes observed in general circulatory (heart rate, systolic and diastolic blood pressure) or physical diagnosis (head and neck, heart, lungs, abdomen, reflexes) were compared to baseline recordings to assess the systemic safety of both preparations. Both preparations had to be administered in once-daily regimen on both sides of the face at bedtime, and the duration of the total treatment period was 12 weeks. Unused medication was collected after the last assessment. 2.1. Statistical analysis Data produced by patients who took an incomplete course of treatment, notably less than 10 weeks, missed more than 24 applications or more than eight applications between weeks 8 and 12 of treatment, were excluded from statistical analysis. The collected and adjusted, sifted data were subjected to analysis using the two sample t-test at the a = 0.05 significance level to determine whether the observed differences in the two treatment modalities would be chance happenings. For the calculated total mean number of comedone lesion counts, the calculated total mean number of inflammatory lesion counts and the total mean number of all acne lesion counts, representing the calculated overall acne severity grade, the Wilcoxon test was used. The assessment results of laboratory data and vital signs as a result of treatment with CTG or tretinoin were subjected to graphic analysis. Differences in the degree of local irritation between treatments were analysed using the Mantel–Haensel Chi-squared test.
3. Results Of 81 acne patients randomly assigned to treatment with CTG, 75 were included for assessment. The original tretinoin group comprised 80 subjects whom 77
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Table 1
Table 2
Demographic characteristics of the global and strictly defined (in italics) CTG and tretinoin study populations
The calculated 50% improvement level of mean baseline comedone lesion counts during treatment
Preparation
CTG Tretinoin Total
No. of patients
75 69 77 69 152 138
Sex
Age
Male Female
Mean ± SD Range (years) (years)
47 44 41 39 88 83
19.9 19.9 19.5 19.6 19.7 19.7
28 25 36 30 64 55
50% improvement level (weeks)
± ± ± ± ± ±
2.8 2.7 3.0 3.0 2.9 2.9
14–26 14–25 14–26 14–26 14–26 14–26
remained for final assessment. Sex distribution and age ranges of this global, intention-to-treat study population are presented in Table 1. Excluding those patients who did not report for assessments at the agreed points of time (CTG, three and tretinoin, four patients) and those showing protocol infringements or dropouts because of adverse effects, a strictly protocol defined study population of 69 patients on CTG and 69 patients on tretinoin remained (see Table 1). The presented data, however refers to the intention-to-treat population of 152 patients of whom 75 were assigned to treatment with CTG and 77 to treatment with tretinoin. 3.1. Assessment of efficacy CTG and tretinoin were shown to have a similar efficacy in the reduction of open and closed comedones (see Fig. 1). At the end of the 12 week treatment
Fig. 1. Improvement of the mean number of open (-A-), closed (-B-) and the calculated total mean number of comedone lesion counts (-♦-) after treatment with CTG (–) and tretinoin (-.-.-.).
Mean lesion counts
CTG
Tretinoin
Open comedones Closed comedones Total comedones
9 7 6
9 9 9
period a 58% reduction of open comedone lesion counts with regard to baseline was obtained with CTG compared to 53% with tretinoin. The difference with a confidence interval (CI) of −4.84 to 14.98 was statistically not significant at the 5% level (P = 0.3). In closed comedones the efficacy of CTG was numerically higher than that of tretinoin in week 12 of treatment; the difference between the obtained improvements of 65% for CTG and 52% for tretinoin were, however, statistically not significant at the P = 0.06 level (95% CI: −0.76 to 22.68). Twelve weeks of treatment with CTG induced a mean reduction of 61% of the calculated total mean number of comedone lesion counts and 55% with tretinoin in the same period of treatment (see Fig. 1). No statistically significant difference could be calculated for these results (P = 0.15, 95% CI: −1.59 to 14.80). Response to treatment as reflected by the 50% lesion reduction of comedone baseline levels, was faster for CTG than for tretinoin in closed (20%) and calculated mean number of comedones (30%) and appeared to be equal in open comedones (Table 2). The effect of CTG or tretinoin on the lesion count of the inflammatory forms of acne, i.e. papules, pustules and nodules, after 4, 8 or 12 weeks of treatment are presented in Fig. 2. In the reduction of papules CTG appeared to be significantly more effective than tretinoin at the P , 0.05 level at all three points of assessment: after 4 weeks, P = 0.04; after 8 weeks, P = 0.01; after 12 weeks, P = 0.0004; 95% CI: 10.74 to 34.20. No statistical differences in efficacy between the two preparations was observed in pustules or nodules at the end of 4, 8 or 12 weeks of treatment. When the speed of efficacy as a function of the duration of treatment was assessed CTG was much more effective than tretinoin in papules and pustules and similar in efficacy in nodules. A 50% improve-
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Fig. 2. Improvement of the mean number of papules (-♦-), pustules (-B-), nodules (-X-) and the calculated total mean number of inflammatory acne lesion counts (-W-) after treatment with CTG (–) and tretinoin (-.-.-).
ment of mean baseline papular or pustular lesion counts was achieved in a shorter time with CTG than with tretinoin (Table 3). When the difference of both treatment modalities on the calculated mean total of inflammatory acne lesion counts was examined, the efficacy at weeks 4 and 8, and at the end of treatment was statistically significant (P = 0.04, or P = 0.01, and highly significantly (P = 0.006; 95% CI: −8.22 to 28.75) in favour of CTG (see Fig. 2). Compared to baseline scores, a mean improvement of about 73% was obtained with CTG compared to about 54% with tretinoin at week 12 of treatment. The 50% reduction rate of the calculated mean total of inflammatory lesions with CTG was obtained with a 60% shorter duration of treatment than with tretinoin (Table 3). When changes in the global, overall acne severity grade, i.e. estimated by the investigator, were recorded as a function of the duration of treatment (see Fig. 3), CTG was reported to induce an improvement of 49% after 12 weeks of treatment compared to baseline, while this improvement was only 39% for Table 3 The calculated 50% improvement level of mean baseline inflammatory lesion counts during treatment 50% improvement level (weeks) Mean lesion counts
CTG
Tretinoin
Papules Pustules Nodules Total inflammatory lesions
5.5 3.5 4 5
8.5 7.5 4 8
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Fig. 3. Percent improvement of the global (-A-) or the calculated overall acne severity grade after (-B-) treatment with CTG (–) and tretinoin (-.-.-.).
tretinoin. The observed difference was statistically significant at the P = 0.02 level, with a 95% confidence interval of 8.22 to 28.75. A significant difference in efficacy between the two treatment modalities in this parameter was also observed at week 8 of treatment (P = 0.014). A response of the global, overall acne severity grade to treatment showing a 50% reduction of baseline recordings was obtained with CTG in week 12 and much slower with tretinoin, calculated to be 2 weeks after the end of treatment. If all recordings of non-inflammatory and inflammatory lesion counts at the four assessment times are put together we will, as a matter of fact, have obtained the actual, calculated overall acne severity grade and its improvements as the result of treatment (see Fig. 3). The mean improvement of this parameter, in the CTG treated group amounted to 64%, compared to 54% for the tretinoin group. After 12 weeks this difference in efficacy was found to be significant P = 0.01 (with a 95% CI: 2.15 to 17.36 using the Wilcoxon test. The 50% reduction level of baseline calculated overall acne severity grade recordings with CTG was reached in week 6 and with tretinoin in week 9 of treatment. A summary of the results of efficacy assessments is presented in Table 4. 3.2. Assessment of safety Of 72 patients treated with CTG and of 73 patients treated with tretinoin who completed 12 weeks of treatment, five patients on CTG and three patients on tretinoin showed adverse effects requiring withdrawal from the study. Of the five withdrawn patients
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Table 4 Summary of the results of acne treatment with CTG and tretinoin Comparison of efficacy Non-inflammatory acne lesion types Open comedones Closed comedones Total comedones Inflammatory acne lesion types Papules Pustules, nodules Total inflammatory Global acne severity Calculated acne severity
No difference No difference No difference CTG better (P No difference CTG better (P CTG better (P CTG better (P
= 0.0004) = 0.006) = 0.02) = 0.01)
on CTG a burning sensation was reported by one, while two patients complained of burning in addition to concomitant inflammation. Another two patients reported irritation accompanied by exfoliation. All three patients on tretinoin who were withdrawn had to do so because of the severity of burning. The reported irritation and burning are the typical cutaneous side-effects of tretinoin; they disappear on discontinuation of treatment. Other adverse effects spontaneously reported by patients during treatment concerned dryness of the skin; this was reported by three patients treated with CTG and one patient on tretinoin. None of the four assessed symptoms of irritation, specifically erythma, induration, scaling and pruritus graded according to the degree of severity from none (0) to very severe (4) showed remarkable or statistically significant changes in either the CTG or tretinoin group. Severity was highest in week 2 of treatment improving steadily until the last week. Erythema and scaling could, however, still be observed in a number of patients at the end of treatment. Severe forms of erythema were present in five patients on CTG and seven on tretinoin, while scaling of the same severity was observed in one patient on CTG and in three on tretinoin. In the 5th assessed symptom of irritation, notably burning, however, treatment with CTG showed statistically significantly less burning than treatment with tretinoin at all weeks of assessment. In the last week of CTG treatment no burning was reported in 61 patients, mild burning in 10 and moderate to severe burning in one patient. For tretinoin, the results were 42, 25 and 6, respectively. Assessment of the general safety parameters, such
as heart rate, blood pressure or physical examination carried out in all 161 patients showed no clinically relevant changes after 12 weeks of treatment in either the CTG or the tretinoin group. Other general safety parameters such as the complete total and differential blood cell count as well as hepatic and renal function tests carried out in 40 CTG and 40 tretinoin treated patients of one centre, likewise showed no clinical relevant changes at the end of treatment.
4. Discussion Considering the similar efficacy of both preparations in open comedones, 58% for CTG against 53% for tretinoin, and the numerically better effect (P = 0.06) of CTG compared to tretinoin in closed comedones, i.e. 63% for CTG compared to 52% for tretinoin, the addition of clindamycin to tretinoin in CTG apparently tends to improve the comedolytic efficacy of tretinoin itself, assuming the vehicle effects to be equal. This assumption is indicated also by the finding that the 50% reduction levels of the calculated total mean number of comedone lesion counts was week 6 for CTG and week 9 for tretinoin. As could be expected from the easy penetrability of open comedones the 50% reduction level of these lesions was roughly reached in the same week 9 of treatment. In closed comedones the increased numbers of anaerobic P. acnes requires the presence of an antibiotic for rapid efficacy. The clindamycin component of CTG appears to have contributed substantially to the improvement in these type of acne lesions, although a possible increased efficiency of the active agents by this particular formulation base cannot be ruled out entirely. In fact the 50% improvement level was obtained at week 7 with CTG compared to week 9 with tretinoin. The percent reduction of 61% for CTG in the total of non-inflammatory lesions of acne demonstrates that the clindamycin addition to tretinoin, as in CTG, does at the same time apparently not affect the efficacy of tretinoin as can be deduced from the 55% tretinoin efficacy in this parameter. The anti-inflammatory and antibacterial activity of clindamycin added to that of the comedolytic efficacy of tretinoin is supposed to be most useful in the treatment of inflammatory forms of acne. This was confirmed by the reported significant differences in efficacy
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between CTG and tretinoin. As was observed, the mean papule reductions from baseline are statistically significantly different at weeks 4, 8 and 12 of assessment. Similar significant difference in efficacy between the two treatment modalities were observed in the calculated total mean number of inflammatory lesion. Considerable differences were also observed in the 50% improvement levels which was about 5.5 weeks for CTG compared to 8.5 weeks for tretinoin in papules and 5 weeks compared to 8 weeks in the calculated total of inflammatory lesions, respectively (Table 4). Why no statistically significant differences in efficacy of the two treatment modalities in pustules and nodules could be demonstrated in this study may have been due to the low number of patients showing sufficiently assessable lesion counts. Those patients with less than 10 lesions at baseline were excluded from statistical analysis. However, the calculated, overall severity score of acne lesions was shown to be closely correlated with the proposed acne severity score of this study notably grade 3 or higher (Pearson correlation 0.60 to 0.78). This means that efficacy assessments of CTG or tretinoin in these ‘deficient’ parameters can possibly only be carried out properly by selecting patients presenting maximal numbers of pustules and nodules or choosing the highest mentioned Cook grades, i.e. classes 6–8 of acne severity. Significant differences in efficacy between the two treatments was also evident from the global as well as from the calculated overall acne severity grades at the various times of assessment. In both parameters, the 50% improvement level was reached several weeks earlier with CTG than with tretinoin. In the estimated, overall acne severity grade this amounted to 2 weeks, whereas in the calculated overall acne severity grade this appeared to be 3 weeks, establishing the rapid onset of action of CTG for this parameter. From the results of the safety assessments it could be deduced that the addition of clindamycin to tretinoin like in the Velac gel formulation, apparently significantly inhibits the burning inherent in treatment with tretinoin alone. A similar experience was reported for the sequential use of tretinoin and clindamycin phosphate years ago [2]. It should also be remembered that an emollient effect of the formulation base could have contributed to such differences in tolerability. This was, however, not clearly evident from the spontaneously reported incidences of burn-
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ing and irritation in five patients on CTG and three on tretinoin. Although the results of the above mentioned safety assessment and the incidence of spontaneously reported adverse effects in the clinical studies might indeed confirm the alleviating influence of clindamycin on tretinoin in the CTG composition, a definite conclusion must be postponed until more clinical experience with CTG is available.
Acknowledgements The authors wish to thank Dr. P. Talsma, Yamanouchi Europe BV, The Netherlands for his statistical calculations.
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