ARTICLE
Systemic antibiotics, such as tetracyclines, are used in the treatment
of moderate to severe inflammatory acne: the mechanism of action appears
to be a result of the combined antibacterial and anti-inflammatory effects
of tetracyclines. In addition to providing potent activity against bacteria
(Propionibacterium acnes) that contribute to the formation of acne
lesions, tetracyclines can limit the release of pro-inflammatory mediators
and chemotactic factors, thus reducing polymorph chemotaxis and, consequently,
localised inflammation [1]. Tetracyclines can also reduce the free fatty
acid content in sebum, which is significant because of the comedogenic
action of free fatty acids and their possible role in the genesis of inflammatory
lesions [1]. Tetracyclines in general and, in particular, lymecycline
(Tetralysal&circR;, Galderma Laboratories), a second-generation semi-synthetic
tetracycline, have been in clinical use for several decades, and are considered
to be safe and effective. Lymecycline has broad-spectrum activity against
aerobic (Gram-positive and Gram-negative) and anaerobic bacteria and consequently
is as effective as other commonly-used tetracyclines, such as doxycycline
and minocycline, in the treatment of moderate to severe acne [2, 3]. In
addition, lymecycline is more water-soluble than other tetracyclines at
all physiological pH values (1 — 7.5) and is therefore
easily absorbed and broken down to tetracycline, lysine and formaldehyde
in the gastrointestinal tract, from where tetracycline diffuses rapidly
into body fluids and penetrates well into body tissues.
A distinct benefit of lymecycline is that it is less ulcerogenic than
doxycycline and oxytetracycline [4]. In addition, lymecycline has a very
low potential for phototoxicity compared with doxycycline (p < 0.02)
[5], and shows higher tolerability, in terms of photosensitivity, compared
with these other tetracyclines [5-7].
Crucially, whereas several rare, yet severe, adverse events have been
reported with minocycline, including life-threatening hypersensitivity
syndrome, serum sickness-like disease and autoimmune reactions such as
drug-induced lupus [8, 9], equivalent adverse effects have not been observed
with lymecycline. Lymecycline is perceived as being well tolerated by
patients and physicians alike, and is associated with a high efficacy
rate and a low incidence of adverse events.
One of the major difficulties with the treatment of many diseases is
a lesser degree of patient compliance when treatment regimens are more
complex. Therefore, the development of once-daily treatments can be of
benefit in patients where compliance is expected to be low.
As a consequence, a double-blind, randomised study comparing the efficacy
and safety of lymecycline 300 mg once daily (od) with lymecycline
150 mg twice daily (bid) in the treatment of moderate to severe acne
vulgaris was performed. In addition, an efficacy comparison between 300 mg
od and placebo was used to provide evidence of assay sensitivity (Tables
I and II).
Patients and methods
Study population
This study was a randomised, multicentre, double-blind, active and placebo-controlled
comparison of three parallel groups: oral lymecycline 300 mg od + oral
placebo od; oral lymecycline 150 mg bid and oral placebo bid. All
treatments were given for a total of 12 weeks.
Male and female patients between the ages of 16 and 40 years
with acne vulgaris were eligible for the study. A minimum of 15 inflammatory
facial lesions and a global severity of at least grade 3 on the Leeds
Revised Acne Grading System [10] were required for inclusion in the study.
Patient evaluation
Five visits were scheduled during the study: at baseline and at weeks
2, 4, 8 and 12. At each visit, the investigator counted the number
of inflammatory (papules, pustules, nodules and cysts) and non-inflammatory
facial lesions (open and closed comedones) individually. Moreover, following
baseline evaluation, an assessment of global improvement was made on each
subsequent visit. Photographs of each subject were taken at baseline and
week 12.
The primary efficacy variable for the dosage assessment was the inflammatory
lesion count at study end. Secondary efficacy variables included inflammatory
lesion counts, total lesion counts and global improvement at all visits.
In the placebo comparison, the primary efficacy variables were inflammatory
lesion counts and global improvement at study end. The secondary efficacy
variables were inflammatory lesion counts, total lesion counts and global
improvement at all visits. Safety was measured by evaluation of experienced
adverse events.
Drug treatment
All treatments were given as two capsules per day, with the same taste
and appearance. Patients receiving lymecycline 300 mg od were given
the active treatment in the morning and a placebo capsule in the evening.
Patients were not permitted to use any treatments liable to interact or
interfere with the efficacy or safety of tetracyclines.
Statistical analysis
For the comparison of lymecycline 300 mg od with 150 mg bid,
the limit of the 95 % Confidence Interval of the difference between
the two forms, in terms of the percentage reduction of inflammatory lesions,
was not to exceed 15 % in favour of the 150 mg bid dose (per
protocol [PP] and intent-to-treat [ITT] population analyses) at week 12.
Intention-to-treat analyses used a last observation carried forward
method. Per-protocol analyses used only evaluable results.
For the superiority of the lymecycline 300 mg od dose over placebo
at week 12, a significant difference in favour of the active treatment
in the two primary efficacy criteria was to be demonstrated (ITT analysis).
Furthermore, all tests were two-sided, at the 0.05 significance level.
All statistical analyses were performed using Cochran-Mantel-Haenszel
(CMH) analysis, stratified for study centre using ridit scores.
The sample size was determined using historical data and the following
working hypotheses: under the assumption of equal efficacy of the two
dosage forms, a sample of 100 evaluable patients in each active treatment
group was calculated to have a 90 % power to demonstrate non-inferiority
using a 15 % margin in terms of reduction in inflammatory lesion
counts at week 12 (eg, 60 % reduction versus 45 %). To allow
for early discontinuations and for major deviations to be excluded from
the per protocol analysis, 120 patients per treatment group were
planned for enrollment. A small placebo group of 60 patients was
included to assess the internal sensitivity of the assay and to formally
demonstrate the efficacy of the 300 mg od form.
This study was conducted in accordance with the ethical principals emanating
from the Declaration of Helsinki and all local regulatory requirements.
Results
Since both ITT and PP analyses showed consistent results, only the ITT
data are discussed here.
Patients
A total of 271 patients were recruited from 25 centres (9 in
France, 6 in Hungary, 10 in Romania). All the treatment groups
were comparable in terms of age and race. Thirty-three patients (12.6 %)
subsequently withdrew due to: subject’s request (2 receiving
lymecycline 300 mg od, 8 receiving lymecycline 150 mg bid
and 2 receiving placebo); lost to follow-up (1 receiving lymecycline
300 mg od, 5 receiving lymecycline 150 mg bid and 2 receiving
placebo); a worsening condition (1 receiving lymecycline 300 mg
od, 3 receiving lymecycline 150 mg bid and 2 receiving
placebo); pregnancy (1 receiving lymecycline 150 mg bid); and
non-serious adverse events (2 in each group — see
safety section).
Efficacy - dosage evaluation
The percentage reduction in inflammatory lesion counts for the two lymecycline
dosing regimen was similar throughout the study (Fig. 1) and, at
week 12, was 62.0 % for lymecycline 300 mg od and 56.4 %
for lymecycline 150 mg bid (95 % CI = — 4.3 — + 8.3 %).
At all other assessments, the lower limits of the 95 % Confidence
Intervals were also above the pre-specified non-inferiority margin of — 15 %.
This demonstrated that lymecycline 300 mg od was non-inferior to
the 150 mg bid treatment regime throughout the 12 week study.
Furthermore, the percentage reduction in total lesion counts from the
baseline assessment verified that lymecycline 300 mg od was non inferior
to lymecycline 150 mg bid at all visits (Fig. 2). By study
end, total lesion counts were reduced by 52 % and 47 % for the
300 mg and 150 mg doses, respectively (95 % CI = — 6.9 — + 6.5 %).
Similarly, no significant difference between lymecycline 300 mg od
and lymecycline 150 mg bid was observed for global improvement scores
at week 12 (Fig. 3). At this time-point, both lymecycline-dosing
regimens resulted in > 70 % of patients showing moderately
improved to completely cleared acne (84/111 patients receiving lymecycline
300 mg od and 76/105 patients receiving lymecycline 150 mg
bid). Global improvement was not significantly different between the two
dosing regimens at any other assessment.
Efficacy - placebo comparison
Percentage reduction in the number of inflammatory lesions demonstrated
a significant superiority of lymecycline 300 mg od over placebo at
week 12 (62.0 % vs 35.6 %, P = 0.0005). Superiority
of active treatment over placebo was also demonstrated at all other visits
in terms of inflammatory lesion counts (Fig.
1).
Significant differences in global improvement were recorded for all
visits between the lymecycline 300 mg od and placebo groups (P < 0.05);
at week 12, 21.6 % of patients receiving lymecycline 300 mg
od (24/111 patients) were cleared or almost cleared compared to 5.8 %
of patients receiving placebo (3/52 patients) (Fig.
3). Percentage reduction in total lesion counts from baseline was
also significantly different (P < 0.05) between these
groups at all assessments in favour of lymecycline 300 mg od (Fig.
2).
Safety
Of the 271 patients entered into the study, 27 (10 %) experienced
adverse events related to treatment. The most
common drug-related adverse events were abdominal pain and nausea; which
showed the same distribution in the three treatment groups. Six patients
(two from each group) withdrew from the study because of a non-serious
adverse event, including headache, genital infection, abdominal pain,
esophagitis and nausea. Importantly, no reports of phototoxic reactions,
autoimmune reactions, hyperpigmentation or vertigo were recorded in this
study.
Discussion
This randomised, multicentre, double-blind study assessed the equal
clinical efficacy and safety of oral lymecycline 300 mg od compared
with lymecycline 150 mg bid, and investigated the superiority of
the 300 mg od dose over placebo.
Previous data have been used to support the suggestion that, for moderate
to severe acne, active treatments should result in at least a 20 %
greater reduction in lesion counts than placebo to establish clinical
superiority. Lymecycline 300 mg od clearly meets this requirement,
decreasing both inflammatory and total lesions far more effectively than
vehicle placebo (Figs. 1 and 2). In addition, both active
treatments also showed statistically significant superiority over placebo
in terms of global improvement.
With regard to the comparative efficacies of the active treatments,
the study was designed to show that the new lymecycline 300 mg od
regimen was not inferior to the 150 mg bid dose commonly prescribed
for moderate to severe acne. Since the difference between reductions of
inflammatory lesion counts achieved by the two dose regimens was well
within the pre-set limit of 15 %, this hypothesis was confirmed.
Moreover, as the other efficacy criteria were similarly unaffected by
dose, it was evident that there was no reduction in lymecycline activity
against moderate to severe acne with the 300 mg od dosing regimen.
The nature and frequency (around 10 %) of treatment-related
adverse events reported in this study were similar to those commonly observed
in previous clinical trials with lymecycline [2, 3, 11], and essentially
the same for both active treatments and placebo. Notably, there was no
evidence that the higher dose increased gastrointestinal disturbances.
This is important because, although such reactions are rarely severe,
they do cause discomfort and may lead some patients to stop their medication.
It is also noteworthy that, although this trial spanned the summer months
¯ a time when tetracycline acne therapy is discontinued by some dermatologists
¯ no phototoxic reactions were reported with either lymecycline-dosing
regimen. It can reasonably be concluded, therefore, that lymecycline 300 mg
od will neither increase the frequency of this or other side effects nor
create specific, unanticipated, safety problems.
Clearly, any new acne treatment should compare favourably, both in terms
of efficacy and safety, with existing therapies. Previous studies have
demonstrated that lymecycline is as effective as minocycline and doxycycline
[2, 3, 10]. It has also been shown that lymecycline is as safe as other
tetracyclines [2, 3].
Moreover, as long-term therapy is usually required for acne, it is essential
that drugs used to treat it are well tolerated and have minimal side effects.
The excellent safety profile of lymecycline 300 mg od suggests that
compliance should not be a problem for its target group of teenagers and
young people. Having to take medication only once a day is also more convenient,
and can improve patient compliance. Additionally, as efficacy is not compromised,
lymecycline 300 mg od represents a promising new treatment for patients
with moderate to severe grades of acne.
Article accepted on 8/10/2002
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