|Year : 2020 | Volume
| Issue : 2 | Page : 76-80
An open-label, prospective, comparative, double-arm clinical trial to evaluate the safety and effectiveness of minocycline extended-release formulation compared with minocycline immediate-release formulation in the management of patients with papulopustular acne
Sushil Pande1, Gaurav Deshmukh2, Dhiraj Dhoot2, Nilesh Andhorikar1
1 Department of Dermatology, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur, India
2 Consultant, Global Medical Affairs, Glenmark Pharmaceuticals Ltd., Mumbai, Maharashtra, India
|Date of Submission||22-Jul-2020|
|Date of Decision||19-Nov-2020|
|Date of Acceptance||19-Nov-2020|
|Date of Web Publication||28-Dec-2020|
Department of Dermatology, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Hingna, Nagpur - 440 019, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Minocycline because of its multiple advantages is considered as first-line therapy in the management of acne. However, conventional formulations of minocycline are associated with multiple side effects, thus limiting its use. Thus, extended-release formulation of minocycline was developed. Materials and Methods: This was an open-label, prospective, interventional, comparative, double-arm study. Patients with papulopustular acne were either received minocycline extended release (ER) 1 mg/kg/day or minocycline immediate release (IR) 100 mg/day for a period of 8 weeks. Safety was assessed by analyzing the adverse event (AE) profile in both the groups. Effectiveness was assessed by analyzing improvement in the mean inflammatory lesion count. Results: A total of 100 patients were included in the study, 50 in each group. A total of four AEs were reported by 2 (4.0%) patients in the ER group, whereas ten AEs were reported by 5 (10.0%) patients in the IR group. The mean inflammatory lesion count in the ER group at baseline was 14.95 ± 3.76, whereas in the IR group, it was 14.52 ± 3.38. Significant decrease in inflammatory lesion count was observed in both the groups during treatment period. Conclusion: The results of this study prove that ER formulation of minocycline is associated with better improvement in acne compared to IR formulation. The study also proves that ER formulation is associated with better safety profile compared to IR profile.
Keywords: Acne, minocycline extended-release, minocycline immediate release, safety
|How to cite this article:|
Pande S, Deshmukh G, Dhoot D, Andhorikar N. An open-label, prospective, comparative, double-arm clinical trial to evaluate the safety and effectiveness of minocycline extended-release formulation compared with minocycline immediate-release formulation in the management of patients with papulopustular acne. Indian J Drugs Dermatol 2020;6:76-80
|How to cite this URL:|
Pande S, Deshmukh G, Dhoot D, Andhorikar N. An open-label, prospective, comparative, double-arm clinical trial to evaluate the safety and effectiveness of minocycline extended-release formulation compared with minocycline immediate-release formulation in the management of patients with papulopustular acne. Indian J Drugs Dermatol [serial online] 2020 [cited 2021 Jun 24];6:76-80. Available from: https://www.ijdd.in/text.asp?2020/6/2/76/305126
| Introduction|| |
Acne is one of the most common dermatological conditions, especially in patients between 12 and 18 years of age with a prevalence rate of more than 85%. Even though acne is not associated with mortality, it has very high morbidity and is associated with very high impact on patient's emotional and psychological aspects.
Oral antibiotics are recommended for the treatment of moderate-to-severe acne vulgaris, and tetracyclines are the most frequently prescribed antibiotic class among dermatologists. Tetracyclines are bacteriostatic, having a dual mechanism of action by inhibiting Propionibacterium acnes proliferation within the sebaceous follicles, and having intrinsic anti-inflammatory effects.,,,
Minocycline because of its good lipophilicity, tissue distribution, and better anti-inflammatory activity has been recognized as highly efficacious for the treatment of acne vulgaris., Its lipophilicity also enhances its absorption, making it less affected by food or dairy intake., Multiple clinical trials have proven the efficacy of minocycline in the management of moderate-to-severe acne. However, minocycline's lipophilicity profile plays a role in its ability to cross the blood–brain barrier. This leads to increase in the incidence of acute vestibular adverse events (AVAEs), such as dizziness, vertigo, and ataxia. Because of these side effects, the use of minocycline is limited in dermatological practice despite its good efficacy.
Hence, an extended-release (ER) formulation of minocycline hydrochloride with weight-based dosing was developed in an attempt to lower the systemic effects associated with minocycline administration without compromising efficacy. In various clinical trials, the safety profile of ER formulation of minocycline was similar to placebo with better efficacy profile., However, there are no comparable clinical trials of ER formulation of minocycline to that of immediate-release (IR) formulation, especially in the Indian setup.
Hence, we conducted this study with an aim to compare the safety and effectiveness of ER formulation of minocycline to that of IR formulation in the management of patients with papulopustular acne.
| Materials and Methods|| |
An open-label, prospective, interventional, comparative, double-arm, and single-center study was conducted at the department of dermatology of a tertiary care hospital in Central India after permission from the institutional ethics committee was obtained. The study duration was 9 months from March to November 2019. Both male and female patients of between 12 and 50 years of age of papulopustular acne were included in the study. Patients with comedonal and nodulocystic acne and other dermatological conditions such as dermatitis and psoriasis were excluded from the study. Oral isotretinoin, other systemic or topical antibacterials, topical retinoids, and other medications that could impact study assessment were not allowed during treatment, and adequate washout period was given for prohibited therapies if patients were on these medications before study enrollment. Sunscreens were allowed.
Visits and follow-ups
At the initial visit, the patients were randomly allocated either to minocycline ER group (ER group), or minocycline IR (IR group), for 8 weeks [Figure 1]. Patients in the ER group received minocycline 1 mg/kg/day, whereas patients in the IR group received minocycline 100 mg/day. After the initial visit, follow-up visits were carried out at 2, 4, and 8 weeks. During each visit, patients were examined for improvement in their inflammatory lesion counts. All the patients were assessed for improvement by qualified blinded evaluator with the help of global severity score based on five-point scale with zero being clear lesions and 4 being severe lesions. Side effect profile in both the groups was assessed.
Primary endpoint of the study was to compare the safety of minocycline ER formulation with that of IR formulation by analyzing all the AEs reported by the patients during treatment and number of patients who discontinued the therapy because of AEs. Secondary endpoints of the study were to evaluate percentage change in inflammatory lesion count at the end of the treatment period from baseline and to evaluate percentage of patients showing treatment success at the end of the treatment period. Treatment success was defined as clear or almost clear lesions on evaluator global severity scale at the end of the treatment.
Descriptive statistics were used to summarize effectiveness and safety endpoints using GraphPad™ Prism version 8 (GraphPad Software Inc., 20057, San Diego, California, USA). Quantitative variables were analyzed using means and standard deviations, and categorical variables were analyzed using frequencies and percentages. P ≤ 0.05 was considered statistically significant.
| Results|| |
Among 120 patients screened, 100 patients who fulfilled the inclusion criteria were included in the study, with 50 patients in each group. Three patients, one in the ER group and two in the IR group, discontinued the therapy due to AEs.
The average age of patients in the ER group was 22.44 ± 5.94 standard deviation (SD) years, whereas in the IR group, it was 21.34 ± 3.84 SD years. Out of 50 patients in the ER group, there were 27 males and 23 females, whereas in the IR group, there were 24 males and 26 females [Table 1].
Both the treatment regimens of minocycline were well tolerated. A total of four AEs were reported by 2 (4.0%) patients in the ER group, whereas ten AEs were reported by 5 (10.0%) patients in the IR group [Table 2]. All the AEs were seen within the first 5 days of therapy. Gastrointestinal disturbance was the most common AE reported by patients in both the groups followed by dizziness, headache, hyperpigmentation, and vertigo. One patient in the ER group discontinued the therapy because of headache, whereas two patients in the IR group discontinued the therapy because of hyperpigmentation, dizziness, and vertigo [Figure 2].
The mean inflammatory lesion count in the ER group at baseline was 14.95 ± 3.76, whereas in the IR group, it was 14.52 ± 3.38. Significant decrease in inflammatory lesion count was observed in both the groups during treatment period. At week 2, the inflammatory lesion count in the ER group was 10.68 ± 2.87, whereas it was 10.72 ± 2.64 in the IR group. Similarly, at week 4, the mean inflammatory lesion count in the ER and IR groups was 6.71 ± 2.46 and 6.93 ± 2.12, respectively [Table 3]. After 8 weeks of therapy, the mean inflammatory lesion count was 2.28 ± 1.5SD in the ER group, whereas in the IR group, the mean inflammatory lesion count was 2.68 ± 1.4SD [Figure 3].
The percentage decrease in inflammatory lesion count in the ER group at the end of 8-week treatment period was 84.75% compared to 81.54% in the IR group [Figure 4].
Treatment success was seen in 82% (n = 41) in the ER group, whereas 78% (n = 39) of patients achieved treatment success in the IR group. There was no statistically significant difference in the ER and IR groups with respect to treatment success. However, there was statistically significant difference between two groups regarding compete clearance of lesions (P = 0.0014). 22% (n = 11) of patients achieved complete clearance (0 score on evaluator global severity scale) of their acne lesions in the ER group compared to none of the patient in the IR group. Nine patients in the ER group and 11 patients in the IR failed to achieve clearance of their acne lesions at the end of 8-week period [Figure 5].
| Discussion|| |
Since the introduction and use of minocycline for the treatment of acne, clinicians have used the same dosage of minocycline as recommended for the treatment of infectious diseases. The pharmacokinetic profile of minocycline is characterized by rapid absorption, a long half-life, and improved penetration and distribution into tissues of high lipid content., Because minocycline is lipophilic, it achieves very high concentrations in sebaceous glands, leading to its higher efficacy in patients with acne. However, this also leads to its increased penetration in to central nervous system (CNS) leading to increased incidence of AVAEs like vertigo, ataxia, dizziness, etc.,, Recognizing the limitations and AEs that occur with these higher exposures, extended-release formulation of minocycline was developed to minimize the systemic exposure and to reduce the AE profile.
ER formulation of minocycline has demonstrated delayed time of maximum concentration (t<Subscript>max</Subscript>, 3.5–4 h) compared with IR minocycline (t<Subscript>max</Subscript>, 2.25–3 h). The ER formulation is also associated with reduced overall exposure as reflected in the lower Cmax (0-24h), area under the curve and less variability in blood levels.
A total of 4% and 10% of patients reported AEs in our study. Even though there was no statistically significant difference between both the groups with respect to AEs, numerically more patients in the IR group reported AEs compared to the ER group. None of the patients in the ER group reported hyperpigmentation or AVAEs. In the IR group, two patients reported hyperpigmentation and two patients reported acute vestibular side effects (dizziness and vertigo). These results are in accordance with a previous study by Stewart et al., where higher doses of minocycline were associated with higher incidence of AEs compared to lower dose of minocycline. In their study, only 10.2% of patients reported AVAEs with minocycline ER 1 mg/kg compared to 23.7% and 28.3% of patients with 2 and 3 mg/kg minocycline, respectively. This difference in AE rate in the two groups could be attributed to the fact that ER formulation of minocycline is associated with reduced systemic exposure and delayed time for maximum concentration, resulting in less accumulation of minocycline in CNS.
Only three patients in our study discontinued the therapy because of AEs. One patient in the ER group discontinued the therapy because of severe headache, whereas two patients in the IR group discontinued the therapy because of hyperpigmentation, dizziness, and vertigo. Similar discontinuation rate was observed in earlier studies.
In our study, there was significant decrease in the mean inflammatory lesion count after 8 weeks of therapy with both ER (84.75%) and IR (81.54%) minocycline. Similarly, the treatment success was achieved by 82% of patients in the ER group, whereas 78% of patients achieved treatment success in the IR group. Stewart et al. and Fleischer et al. reported 43.1%–56.8% decrease in inflammatory lesion count with minocycline ER. Treatment success in both the studies was in the range of 15.9%–30.0%., Similarly, Harrison, Ocampo-Candiani et al., Grosshans et al., and Khanna in their studies reported decrease of 36.08%–68.21% in inflammatory lesion count with minocycline IR. Treatment success in all these studies was in the range of 47.9%–84%.,,,
The results reported for minocycline ER in our study are comparatively better than the previous studies by Stewart et al. and Fleischer et al. This could be attributed to the fact that the patients in our study were having milder disease compared to previous studies. The mean inflammatory lesion count at baseline in our study was 14.52–14.95, whereas it was 38.8–47.0 in a study by Stewart et al. and 38.4–39.1 in the studies by Fleischer et al.,
In our study, both the formulations of minocycline were associated with significant decrease in the mean inflammatory lesion count and higher treatment success at the end of the treatment period. There was no statistical difference between both the groups; however, numerically more patients in the ER group showed improvement in their acne compared to IR group. None of the patients in the IR group achieved complete clearance of acne lesions, whereas 22.44% of patients achieved complete clearance of acne lesions with minocycline ER. This difference in complete clearance of acne lesions was statistically significant with P value equal to 0.0014.
| Conclusion|| |
To our knowledge, this is the first Indian study directly comparing the efficacy and safety of ER formulation of minocycline to that of IR formulation. The results of this study prove that ER formulation of minocycline is associated with numerically better improvement in acne compared to IR formulation. The study also proves that ER formulation is associated with better safety profile compared to IR profile.
The findings of this study further strengthen the following facts. Minocycline because of its high lipophilicity achieves high concentrations within the lipid-rich follicle, with steady accumulation over time as administration is continued. Minocycline ER because of its weight-based dosing (1 mg/kg/day) allows for a reduction in both peak serum levels and cumulative exposure, which correlates with a lower risk of AEs. Clinical efficacy of minocycline in acne vulgaris directly correlates with a dose–response curve, which is dependent on a progressive increase in follicular concentration over time, rather than the need to achieve high serum levels that are more immediate in onset.
We would like to acknowledge the help of Glenmark Pharmaceuticals for supply of study drugs required for this investigator initiated study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]