A comparison of the efficacy and safety of lymecycline and minocycline in patients with moderately severe acne vulgaris

ARTICLE

Tetracyclines are the most commonly used oral treatment for acne vulgaris [1] and are the agents of choice for moderate to severe inflammatory acne that fails to respond to topical therapy [2-4]. The first generation tetracyclines include tetracycline, oxytetracycline, chlorotetracycline and demethylchlorotetracycline. Introduction of the second generation (hemi-synthetic) cyclines such as doxycycline, lymecycline and minocycline has brought pharmacokinetic improvements, including better oral absorption, enhanced tissue penetration and slower elimination. As a result, therapeutic regimens can be simplified, allowing once daily drug administration.

The efficacy and safety of oral minocycline in the treatment of acne vulgaris is well established [5-7], with minocycline displaying similar efficacy to doxycycline [6-8] and superior efficacy to tetracycline [1, 9] in reducing follicular colonisation by staphylococci and propionibacteria and suppressing inflammatory acne.

In addition to the adverse effects characteristic of tetracyclines as a class, minocycline use has been associated with a number of drug-specific reactions, including vestibular disturbances [10] and blue-black hyperpigmentation affecting the skin, mucous membranes, permanent teeth and internal organs [11-13]. Minocycline has also been implicated in immunologically-mediated reactions, with reports of systemic lupus erythematosus and auto-immune hepatitis [14-16], hypersensitivity syndrome [16], Sweet's syndrome [17] and eosinophilic pneumonia [18-20]. The possibility of such serious reactions, albeit very low [21], needs to be taken into account when selecting an antibiotic treatment for acne, and it has been suggested that minocycline should be reserved for use in those patients who do not respond to first line agents such as tetracycline [21-23].

Lymecycline (Tetralysal^®) is one of the most widely prescribed tetracyclines in Scandinavia [24] and has been shown to produce significantly higher serum concentrations than doxycycline in healthy volunteers [25]. As early as 1968, lymecycline was reported to be effective and well tolerated in the treatment of acne vulgaris, demonstrating similar efficacy to tetracycline in a small-scale open-label study [26]. Although lymecycline is now available commercially for the treatment of acne vulgaris, published data on its efficacy in this indication are limited [26, 27]. For this reason, we conducted a double-blind, randomised study to compare the efficacy and safety of lymecycline with that of minocycline in patients with mild to moderate acne.

Methods

A randomised double-blind and double-dummy study was conducted at five centres in Europe to investigate the efficacy and safety of lymecycline in comparison with that of minocycline.

Subjects

Male and female adolescents and young adults, aged between 12 and 32 years, presenting with moderately severe acne (grades 1-5 according to the Leeds technique) [28] were recruited into the study. Patients were required to have 15-120 inflammatory facial lesions with, at most, 2 nodules of diameter > 1cm, and fewer than 60 non-inflammatory lesions. Patients with acne conglobata, acne fulminans or secondary acne were excluded from the study, as were those who had undergone treatment with topical anti-acne/anti-inflammatory agents or systemic anti-inflammatory/antibiotic agents within the previous 4 weeks. Treatment with oral isotretinion had to have been discontinued 6 months before. In addition, patients receiving drugs likely to interact with cyclines (retinoids, anticoagulants, antacids, iron preparations and hepatic enzyme inducers) were excluded. All patients gave their written informed consent to participate in the study, which was performed in accordance with the Declaration of Helsinki and with Good Clinical Practice guidelines.

Study treatments

Patients were randomly allocated to one of two parallel treatment groups. Patients received oral lymecycline, 150 mg twice daily for the first two weeks followed by 150 mg once daily for the next 10 weeks, or oral minocycline, 100 mg once daily for the first two weeks followed by 100 mg every other day for the next 10 weeks (the dosage recommended by Lederle and Galderma, France). A double-dummy technique involving administration of placebo minocycline capsules with lymecycline and placebo lymecycline capsules with minocycline was employed to ensure the blinding of the study. Patients were instructed to avoid extensive exposure to the sun or ultraviolet rays during treatment to prevent problems of photosensitisation. No anti-acne treatment, other than the study drug, was permitted during the study, and systemic antibiotics, systemic/topical corticosteroids and drugs liable to interfere with cyclines were avoided. Patient compliance was assessed by counting capsules returned to the physician.

Clinical assessments

Patients were assessed on study inclusion (week 0) and after 4, 8 and 12 weeks of treatment. Inflammatory lesions (papules, pustules and nodules) and non-inflammatory lesions (comedones and microcysts) were counted on the forehead, cheeks and chin. The severity of acne was graded using a modification of the Leeds technique [28]: ­ 0: clear; 0.25-0.75: comedones present; 1-2: comedones present and a moderate number of papules and pustules; 3-5: numerous papules and pustules and occasional extended inflamed lesions; 6-10: nodulo-cystic acne or acne conglobata with severe, painful cystic lesions. At the final visit, the investigator and the patient assessed the efficacy of treatment according to the following global improvement scale: ­ 1: worsened; 0: unchanged, 1: improved; 2: much improved; 3: cleared.

At each visit, the patient was asked about the occurrence of adverse events and at the end of treatment the patient and the investigator assigned a global assessment of tolerance to the study drug according to the following scale: ­ 1: poor ­ major, significant side effects which interfered with activity, 0: fair ­ minor, non-troublesome side effects; 1: good ­ no side effects.

Statistical analyses

The sample size of 144 was planned to ensure that there were 67 evaluable patients per treatment group. This was to enable the investigators to detect a 15% difference in the percentage reduction in the inflammatory lesion count with an 80% probability using a two-sided test performed at the 0.05 significance level.

The inflammatory lesion count at week 12 was the primary criterion of efficacy. Lesion counts were normalised by transformation into square roots and subjected to an analysis of covariance (ANCOVA). In addition, the percentage reductions in lesion counts were placed in the following categories of improvement using the Mills and Kligman scale [29]: > 75%: excellent; 50-75%: good; 25-50%: fair; ¾ 25%: poor. Changes in lesion count and acne severity, as well as patients' and investigators' global assessments of efficacy and tolerability, were compared between treatments using the Cochran-Mantel-Haenszel test, with a probability value < 0.05 representing statistical significance. Both "per protocol" and last assessment ("intention to treat"; ITT) efficacy data were analysed. All patients who received treatment were included in the safety analysis.

Results

Patients

A total of 144 patients (86 male and 58 female), aged 12 to 32 (mean 19) years, were recruited into the study and the two treatment groups (lymecycline: n = 71, minocycline: n = 73) were well matched for demographic characteristics at entry (Table I). Similar numbers of patients discontinued lymecycline treatment (n = 8) and minocycline treatment (n = 10) during the study. The most common reasons for discontinuing treatment were non-medical (n = 11). Medical reasons accounted for slightly more discontinuations from minocycline than from lymecycline. Treatment failure accounted for two discontinuations of minocycline and adverse events caused four minocycline recipients and one lymecycline recipient to withdraw from treatment. Thus, 63 patients in each treatment group completed the study. Treatment compliance was good, with only four patients having a compliance of less than 70%.

All 144 patients were eligible for the ITT efficacy analysis and 143 patients (70 lymecycline and 73 minocycline) were evaluable for safety analysis. A total of 134 patients (65 lymecycline and 69 minocycline) were evaluable for the per protocol efficacy analysis.

Lesion counts

The mean number of inflammatory lesions was progressively and significantly reduced by both treatments at each time point (Fig. 1) and there were no significant differences between the treatments at any time point. At the end of the study, the overall reduction in the inflammatory lesion count was similar with lymecycline (50.6%) and minocycline (52.2%) on ITT analysis. Similarly, the mean number of non-inflammatory lesions was reduced significantly at all visits during treatment with both lymecycline and minocycline (Fig. 2) and there were no significant intergroup differences at any time point. At study end, the overall reduction in the non-inflammatory lesion count was 40.6% with lymecycline and 32.2% with minocycline (ITT analysis), a trend in favour of lymecycline which approached statistical significance (p = 0.093).

A similar pattern of results was found for the total lesion count. Both treatments reduced the mean total lesion count after 4, 8 and 12 weeks' treatment and at study end, but there were no significant differences between the two treatments. The overall reduction in the total number of lesions at study end was 44.5% with lymecycline and 42.9% with minocycline (ITT analysis).

The improvement in lesion count, categorised according to the method of Mills and Kligman [29], is shown in Table II. The majority of patients showed good or excellent improvements in inflammatory lesions (58% of lymecycline and 63% of minocycline recipients). For non-inflammatory lesions and total lesions, slightly fewer patients achieved good or excellent results than for inflammatory lesions. However, a somewhat higher proportion of lymecycline than minocycline recipients achieved good or excellent results for non-inflammatory lesions (46 vs 30%) and for total lesions (46 vs 41%). However, these results were not statistically significant.

Global severity

Both treatments progressively improved the mean global acne grade at each timepoint compared with baseline (Fig. 3). There were no significant inter-treament differences in the reduction in acne severity at any timepoint. At the end of the study, the mean percentage reduction in global acne severity was 42.4% with lymecycline and 47.9% with minocycline (ITT analysis).

Global improvement

Global assessments of efficacy made by the investigator and the patient after 12 weeks of treatment revealed no significant inter-treatment differences. The condition of the majority of patients was improved or much improved in both treatment groups at week 12 (Table III). The investigator considered that the global condition of 87.9% of lymecycline recipients and 85.7% of minocycline recipients was improved by week 12 (ITT analysis). Patient assessments were generally in agreement with those of the investigator: 84.6% of the lymecycline patients and 83.1% of the minocycline patients considered their own condition to have improved. The 'per protocol' results reflected those of the ITT analysis.

Safety

Both treatments were similarly well tolerated. The incidence of adverse events was comparably low in each treatment group, with 21.4% (15/70) of patients in the lymecycline group and 26.0% (19/73) in the minocycline group experiencing a total of 17 and 27 adverse events, respectively. The great majority (97.7%) of these were mild or moderate in nature. Eleven adverse events occurring with lymecycline and 14 occurring with minocycline were considered to be at least possibly related to the study treatment, while the remaining 6 and 13 adverse events, respectively, were unrelated to treatment. None of the treatment-related adverse events were severe or serious.

The most common type of adverse events were gastrointestinal disorders, and these occurred less frequently with lymecycline (n = 4) than with minocycline (n = 7). Of those that were attributable to the study treatment, nausea (n = 5), diarrhoea (n = 3) and other gastrointestinal disorders (n = 2) were the most frequently reported. Adverse dermatological events were somewhat less frequent in the lymecycline group (n = 2) than in the minocycline group (n = 4). Those that may have been related to treatment were reported in two lymecycline recipients (dry skin, hair disorder) and in one minocycline recipient (acne). There was one report of a photosensitivity reaction, which occurred in the minocycline treatment group. Adverse dermatological effects [acne flare (n = 2); eczema flare (n = 2)] caused four minocycline recipients to discontinue study treatment.

There were no significant inter-treatment differences in investigators' and patients' global assessments of drug tolerability after 12 weeks of treatment. The investigators did not consider any patient to show poor drug tolerance and rated tolerance as good in 86.4% of lymecycline and 87.5% of minocycline recipients. Patients considered that tolerance was good in 86.4% of the lymecycline group and 84.7% of the minocycline group.

Discussion

In this double-blind, multicentre, randomised study, lymecycline was shown to be as effective as minocycline for the treatment of moderate acne vulgaris. Both treatments reduced the differential lesion count (inflammatory, non-inflammatory and total) and improved overall acne severity. There were no significant differences between the two treatments in terms of the reduction in inflammatory, non-inflammatory or total lesion count or the global improvement at any time during the 12-week study.

Both treatments were well tolerated, with no reports of serious or severe adverse effects that were attributable to the study drugs. The most common adverse events associated with treatment, as expected, were of a gastrointestinal nature. However, dermatological events such as acne and eczema flare caused withdrawal of four patients, even though these events were not clearly attributable to treatment.

Lymecycline has previously been reported to offer similar efficacy to tetracycline [26], minocycline [27] and doxycycline [27] in the treatment of acne vulgaris. In an open-label study in which 21 patients with acne vulgaris received lymecycline for at least 10 weeks, 90% of patients reported reduction or clearance of their lesions [26]. More recently, in a randomised comparison of lymecycline, minocycline and doxycycline in predominantly inflammatory acne vulgaris, global improvement (lesion reduction or eradication) was noted in 93% of patients (n = 33) after 12 weeks' treatment with lymecycline [27]. The global improvement observed by investigators in the present study of lymecycline was similarly high (88%).

The efficacy of minocycline [5-7, 30-32] in the treatment of acne vulgaris is more firmly established than that of lymecycline and the improvements obtained in this study are consistent with earlier findings, with minocycline reducing inflammatory lesions by 51% and non-inflammatory lesions by 41% compared with baseline.

While it may be argued that the lack of any significant treatment difference in the present study reflects an inadequate sample size, this seems unlikely. The study had an 80% power of detecting differences of approximately 13% in the reduction in inflammatory lesion count, based on the variability observed in the patient population. The 90% confidence interval for the observed difference in the percentage reduction from baseline in inflammatory lesion count at the study endpoint (ITT analysis) did not exceed 6% in favour of lymecycline or 9% in favour of minocycline. It is therefore unlikely that there is any clinically relevant difference in efficacy, as assessed according to this key parameter, between the two treatments. In addition, efficacy was determined by a number of different techniques and scales, and by both ITT and protocol statistical analyses, all of which produced comparable results.

The incidence of adverse effects seen with lymecycline in the present study (21%) was comparable to that previously reported (19%) [26]. As in the earlier study, the type of adverse effects predominantly associated with lymecycline were gastrointestinal disorders and dermatological complaints. The absence of photosensitivity with lymecycline concurs with the results of a previous investigation of the phototoxicity of lymecycline and doxycycline [24]. No photosensitivity was observed in 15 volunteers who received lymecycline 0.6 g twice daily for 3 days, in contrast to doxycycline which was found to have significant phototoxic potency.

Effective management of acne requires prolonged treatment for months if not years. It is therefore important that anti-acne therapy is well tolerated during long-term use. Occasional reports of serious reactions with minocycline, including autoimmune hepatitis and drug-induced lupus erythematosus [22], need to be placed in context: minocycline is one of the most commonly employed agents for the treatment of acne vulgaris and is routinely administered for long periods. Although it is unclear whether tetracycline can cause similar reactions, this agent is generally preferred over minocycline for the treatment of acne vulgaris. Lymecycline, on account of its conversion to tetracycline in the gastrointestinal tract, is likely to share the same safety profile as its parent compound, and may thus be regarded as a suitable first-line, oral treatment.

CONCLUSION

In the present study both lymecycline and minocycline effectively reduced moderately severe acne vulgaris over a 12-week treatment period and were well tolerated. Lymecycline demonstrated similar efficacy and tolerability to minocycline.

Acknowledgements

We acknowledge the assistance of BPCI clinical services (Dr G. Brion) in monitoring the study and conducting the statistical analysis. The study was organised and funded by CIRD Galderma, Sophia Antipolis, France.

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