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A randomised, double-blind, vehicle-controlled study to evaluate the efficacy and safety of MAS063D (Atopiclair ®), in the treatment of mild to moderate atopic dermatitis |
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European Journal of Dermatology. Volume 15, Number 1, 31-6, January-February 2005, Therapy |
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Author(s) : G Belloni, S Pinelli, S Veraldi , European Institute of Dermatology, Viale Puglie 15, 20137 Milan, Italy, Institute of Dermatological Sciences, I.R.C.C.S., University of Milan, Via Pace 9, 20122 Milan, Italy Fax: (0039) 50 32 07 79.. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Summary : MAS063D (Atopiclair ®) is a hydrolipidic cream that has been developed for the management of atopic dermatitis (AD). The putative active ingredients of MAS063D are hyaluronic acid, telmesteine, Vitis vinifera, glycyrrhetinic acid. A five-week study in 30 adult patients with mild to moderate AD showed that MAS063D offered significant benefits over a vehicle-only control. MAS063D improved the total body area affected (17.2% → 13.2%, p <\; 0.001), itch score (2.7 → 1.3 on a 10-point scale, p \= 0.001) and EASI score (28.3 → 24.3, p \= 0.024) after 22 days treatment compared to baseline. The patients’ opinion of MAS063D (patient’s view of itch control, and view of study substance) was rated by participating patients as significantly better than control (p \= 0.008, p \= 0.042 respectively). Based on these preliminary results in a small scale study, it is suggested that MAS063D is a possible new treatment option for improving signs and symptoms in adults with mild to moderate AD. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Keywords : atopic dermatitis, eczema, emollient, itching, MAS063D | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ARTICLE
Auteur(s) :, G Belloni1, S Pinelli1, S Veraldi2,* 1European Institute of Dermatology, Viale Puglie 15,
20137 Milan, Italy accepté le 7 Octobre 2004 Atopic dermatitis (AD) is a pruritic, inflammatory disease, which significantly reduces patients’ quality of life [1]. Typical clinical presentations include erythema, oedema and vesicles in the acute/subacute phase, and crusts, scaling, dryness/xerosis and lichenification in the chronic phase. Skin lesions are generally itchy and this is a key complaint for many patients.AD generally appears during early childhood. The worldwide prevalence in children has been estimated at 10-15% [2] and 7-21% [3]. Several signs and symptoms of AD often improve by early adulthood, yet the disease may persist and its prevalence in adults has been reported to vary from 1-3% [4] and 0.1-10% [5].Guidelines for the management of atopic dermatitis have been developed by US [6] and UK [7] dermatological societies. Systematic literature reviews of AD management [4], the epidemiology of the disease [5] as well as evidence-based reviews of treatment options are also available [8]. A wide-ranging approach to the management of AD is generally recommended; it includes: skin hydration by means of emollients, topical corticosteroids, and the removal or treatment of exacerbating factors, e.g. allergens, irritants, emotional stress and bacterial superinfection [6]. Therapy of mild to moderate AD typically starts with liberal emollient use, which should be continued even if the disease improves or another treatment is being used [9]. Topical corticosteroids provide immunosuppressive, anti-inflammatory and antipruritic effects [3] and, in combination with emollients, represent the mainstay of therapy [4, 6]. However, prolonged corticosteroid therapy should be decreased or avoided where possible because of side effects (skin atrophy, secondary viral and bacterial infections and acne). Furthermore, corticosteroids must be used with caution in children, because of the potential suppression of the hypothalamic-adrenal axis and body growth [3]. Minimising steroid use where possible is a priority for both clinicians and patients. Other treatment options may include oral antihistamines [2], topical and/or oral antibiotics where secondary infection is involved [4, 6]. Treatment options for more severe cases include systemic corticosteroids, immunomodulating drugs (e.g. cyclosporin) and phototherapy [10]. Topical immunumodulators (e.g. tacrolimus [1] and pimecrolimus [10]) are used for all cases of AD, ranging from mild to moderate to severe, and are the mainstay of therapy, together with corticosteroids.MAS063D is a hydrolipidic cream developed for the relief and management of signs and symptoms, such as pruritus and erythema, of various inflammatory and allergic skin disorders. MAS063D contains lipid and water soluble moisturizers, which provide a deep and soothing replenishment of essential moisture to the skin. This barrier type of moisturizing action helps to protect the injured tissue from further exogenous insult. Components of MAS063D may provide unique benefits as single substances. Hyaluronic acid induces tissue hydration [11] and provides lubrication benefits in ocular surgery as well as orthopedic surgery. Telmesteine [12] and Vitis vinifera [13] have anti-proteasic activities, inhibiting harmful enzymes that are exuded by damaged skin and glycyrrhetinic acid is reported to have an anti-inflammatory action [14].The objective of this study was to assess the effect of MAS063D on the symptoms and signs of AD. The main outcomes of interest were the itch score, affected area and EASI score.Patients and methodsParticipantsParticipants were considered eligible if they met the following inclusion criteria: fair/light skin without recent suntan, > 16 years, mild to moderate eczema [15], grading according to Rajka and Langeland’s criteria of 3.0-7.5 [16], with < 20% cutaneous surface involvement. Patients were required to give written informed consent. Female sexually active patients were required to test negative in a pregnancy test and agree to use active birth control during the study and for two weeks afterwards.Patients receiving systemic medications (antihistamines, corticosteroids, NSAIDs, or other topical and systemic investigational drugs) were maintained on the medications at a constant dose throughout the study. Patients receiving topical medications (e.g. antihistamines, corticosteroids, NSAIDs) were taken off these medications in a wash-out period of 7 days before the start of the study, such that no patients were using these medications 7 days before the study or during it. The wash-out periods for patients on phototherapy or tranquilisers were 4 weeks and 5 days, respectively. The following patients were excluded: patients with a cutaneous or systemic viral (including HIV or AIDS), mycotic or bacterial disease requiring a topical or systemic therapy, patients with a systemic disease, patients with insulin-dependent diabetes mellitus uncontrolled by diet, pregnant or breast-feeding patients, patients with another skin condition other than atopic dermatitis, patients with a history of allergy to the ingredients of MAS063D, patients previously treated with MAS063D, patients with a history of substance or alcohol abuse or any other psychological condition that may have adversely affected their cooperation with the study, patients with friends or relatives working at the study centre. Patients attended a dermatology clinic and data were collected at this location. Thirty patients were recruited. The study was approved by and conducted according to the guidance of the Institution’s Institutional Review Board. InterventionsPatients were examined at visit 1 (baseline) and a demographics questionnaire (age, gender, ethnicity, history of exposure to irritants or other factors that may contribute to atopic dermatitis) was completed. Patients were then randomised to receive MAS063D or vehicle-only control, according to their order of entry into the study. MAS063D and control were presented in identical, blindly, pre-labelled containers. Each container was labelled with the patient’s study number and patients, observers and all trial personnel were blinded to the study code.Randomisation was carried out in blocks of six patients using the random number generator in Microsoft Excel®. If the number generated started with an odd number, that patient was given MAS063D. If the number generated started with an even number, that patient was given control. If the first three patients in one block were assigned to one side of the study, then the subsequent three patients would be assigned to the other side, to enable balance within each block of six. This procedure gave genuinely random patterns; because the tubes were blindly labelled, the investigator/patient could not predict the identity of the sixth substance. The jars containing MAS063D or control were presented blindly, labelled with identical directions for use, i.e. for the contents of the jar to be used on the affected area. Patients applied the study substance for the first time following visit 1, and three times daily thereafter for 21 days. Patients were examined again at 8 days (visit 2), 15 days (visit 3) and 22 days (visit 4) after visit 1. Response to therapy was recorded at each visit. At visit 4 patients stopped using the cream and were re-examined two weeks later at visit 5. ControlThe control jar contained only the emollient cream base that is used as the vehicle for MAS063D; this would normally be expected to have some beneficial effect.OutcomesOutcomes included individual measurements of clinical symptoms and signs: severity of atopic dermatitis (graded according to the Rajka and Langeland criteria) [16] percentage of body area affected, and the EASI score [17]. The clinical symptoms measured were: itch score, hours of sleep, the patient’s view on how much the cream helped the pain and itch, and whether the patient would choose to use the cream again.The itch score was measured on a 10 cm visual analogue scale (without anchor points). The distance between the upper end of the scale (no itch) and the patient’s mark on the scale was measured by the investigator. The affected area assessment was performed by dividing the body into four regions: head and neck, upper limbs, trunk and lower limbs. The percentage of the region affected was then multiplied by the relevant factor to calculate the overall score. Questions to the patients were given in a consistent way according to the structure of the Case Record Form. Adverse events observed by the clinicians or reported by patients were assessed by the study investigators. No laboratory or instrumental tests were performed. StatisticsThirty patients were included in this preliminary study, in two groups of fifteen patients. Power calculations for the determination of sample size were not performed. Groups of fifteen patients were considered large enough to gain an initial impression of the difference between the two groups.Efficacy measures in the treatment groups (the differences in the score of the outcome variable) were compared using the Wilcoxon rank sum test [18] on changes from baseline (visit 1) for visits 2 to 4, and separately from visit 4 (when treatment was stopped) to visit 5 (follow up visit two weeks later). Patients’ views of treatments in the two groups were compared using the Cochran-Armitage test for trend in a 2 x k contingency table with ordered categories (also known as the trend test for a contingency table) [19]. The statistical package used was SAS, version 8.2 for Windows (SAS Software Inc., Cary, NC). ResultsRecruitmentThirty patients were randomised between the study groups. None was lost to follow up and all patients were included in the final analysis. The enrolment period was from 9th December 2002-7th February 2003. The last patient completed the study on 18th March 2003. Fifteen patients did not consent to involvement in the study for various reasons.Baseline dataSixteen men and 14 women, all Caucasian, were recruited (table 1( Table 1 )). Overall median age was 23 (mean age 28). Patients had experienced atopic dermatitis for mean 13 years (median 9 years) and their current episode had lasted between 3 and 6 months. The two groups were comparable in terms of age, sex, duration of condition, duration of current episode and initial severity.Table 1 Baseline data: patients demographics
Numbers analysedThe clinical outcomes of both patient groups (MAS063D n = 15, control n = 15) were analysed on an intention-to-treat basis. Further ancillary analysis was not performed.OutcomesThe values of the variables chosen as outcomes were similar at baseline between the two groups (table 2( Table 2 )). A statistical comparison (Wilcoxon rank-sum test) between the groups was performed, confirming their similarity as the two groups were random samples from the same population.A statistical comparison of the change in outcome variables was made for the control group, who received the vehicle cream alone (table 3( Table 3 )). The only outcome variable to differ significantly (p < 0.05) from baseline was the itch score at visit 4. There were no statistically significant changes in any outcome variable at any other visit compared to baseline. Within the MAS063D group, a general trend of improvement in all
clinical outcomes, except for sleep, was noted from baseline
through visits 2, 3 and 4. The results in terms of improvement
between visits 1 and 4 are shown in table 4( Table 4 ). Statistically significant improvements
were observed for several of the outcomes between visits 1 and 4.
These were the itch score (at visits 3 and 4), affected area and
the EASI score (at visit 4).
Table 3 Control group: change in outcome variable at visit 4 compared to baseline. Increases are shown as negative, decreases as positive
Table 4 MAS063D group: Change in clinical outcomes between visit 1 and visit 4 (22 days)
Efficacy: patients’ view of study substanceAt the end of the study, patient opinion was recorded. MAS063D registered a positive impact on 93% of the patients using it, as they stated a preference toward using it again, with 33% saying they “would” use the cream again and 60% responding they “may” use the cream again. Conversely in the vehicle control group, 60% of patients replied that “may” use the cream again while 33% stated they “would not” use it again. The greater patient acceptability of MAS063D was statistically significant compared to control (p = 0.04 by the Cochran-Armitage test).Patients were also asked at the end of the study for their view of how good they thought the cream was at relieving the pain and itch of their atopic dermatitis. Patients’ opinion of MAS063D on pain and itch was significantly better than the control group (p = 0.008 by the Cochran-Armitage test). In the MAS063D group, 93% patients registered a positive opinion (8/15 (53%) patients stated “quite good”, 6/15 (40%) patients stated “slightly helped”). Patients using control were less satisfied; 53% registered a positive opinion (2/15 (13%) stated “quite good”, 6/15 (40%) stated “slightly helped” and the remainder (7/15, 47%) stated “did not help”. Follow-up visitsA decline in the improvement of all clinical outcomes (except sleep which did not improve) was recorded between visit 4 (end of treatment) and visit 5 (follow-up, two weeks later). This effect was greater in the MAS063D group than in the control group, and the differences were statistically significant in the affected area, EASI and itch score measurements (table 5( Table 5 )).Table 5 Decline in clinical improvement during follow up between visit 4 and visit 5 (14 days)
Adverse eventsNo observed or reported adverse events were recorded in either patient group.DiscussionMAS063D demonstrated statistically significant changes in outcome variables when compared to the control group. These outcomes were important signs and symptoms of AD: affected area, EASI and the itch score and the investigators believe that the statistical outcomes reflect clinically important outcomes. The control group itself, as an emollient, would normally be expected to show some beneficial effect, and this was recorded at visit 4 for the itch score. MAS063D therefore demonstrated improvement over a standard treatment and this statistical difference in the outcome measurements was reflected by the patients’ desire to use MAS063D in the future. It is concluded therefore that, given the small scale of the study, MAS063D may potentially be a new treatment option for atopic dermatitis.Although the patient numbers in the present study were lower than in comparable studies, two groups of fifteen patients were considered sufficient to give an initial impression of the effects of the study medication. For the patient it is important to get relief in the short-term from the symptoms and signs of AD, so the first few weeks after treatment starts is often the most important period of a study. The present study was of a comparable duration (5 weeks) to previous studies of treatments for AD, many of which have lasted between 3 weeks to 6 weeks [3, 20-23]. The patients included in this study were a fair representation of the adult AD population at the study centre. The benefit given by MAS063D became progressively apparent between 15 and 22 days of use. The greater decline in improvement observed 2 weeks following completion of treatment with MAS063D compared with the control group reflects the fact that improvements between visit 1 and visit 4 had been greater in the MAS063D group. The deterioration in clinical outcomes did not exceed the improvements seen between visits 1 and 4. The lack of observed or reported adverse events in either group indicates that MAS063D and the emollient alone were well-tolerated. The rationale for using MAS063D differs from previous therapies, which have mainly sought to pharmacologically adjust the atopic dermatitis. MAS063D aims to improve the environment of the skin by protecting the area of atopic dermatitis from insult by free radicals and skin-damaging enzymes, and by providing a protective, moisturising barrier at the skin surface. MAS063D (trade name Atopiclair®, Sinclair Pharmaceuticals, Godalming, UK) is an emollient cream, containing lipid and water soluble moisturizers, that also includes additional ingredients designed to improve the skin environment. Hyaluronic acid is a glycosaminoglycan (mucopolysaccharide) found in healthy connective tissue. It is included in MAS063D because it induces tissue hydration [11] and traditionally it has been used as a lubricant in other areas of medicine such as ocular surgery and orthopedic surgery. The molecule is very hygroscopic and the water held can be delivered directly to the skin for a powerful moisturising action. Its additional barrier mechanism may help to maintain an integral skin and protect the wound site. Studies indicate that hyaluronan chains have a major organisational role within the collagen bundle itself [24] and may play a role in the migration of cells at wounds [25]; hence overall the molecule may optimise conditions for recovery of the skin [11]. Vitis vinifera contains procyanidins, antioxidants that can protect tissue from damage by free radicals. This has been demonstrated in vitro [13] and in vivo, where it protected patients from UV damage to the skin [26]. Procyanidins have been examined at the vascular endothelium, where they help to prevent oxidative damage [13, 27]. In addition to this anti-oxidant function, procyanidins form a barrier to the concentration of elastase, collagenase, hyaluronidase, and ß-glucuronidase, enzymes involved in the destruction of elastin, collagen and hyaluronic acid proteins [28]. Telmesteine has a scavenging action on free radicals [29] and may offer protection against oxidising agents responsible for epithelial damage [12]. These ingredients have been included so that MAS063D can contribute to an improved skin environment, with the aim of relieving symptoms and signs of AD. This study has shown that based on both objective measurements and patient opinion, MAS063D provided an effective, corticosteroid-free option for managing symptoms and signs of mild to moderate atopic dermatitis. AcknowledgementsThe authors thank David Thompson (of David Thompson Applied Statistics) for performing the statistical analysis and Mark Carew (freelance medical writer) for non-authorial editorial assistance in collating information and drafting the manuscript for publication.The study was supported by a grant from Sinclair Pharmaceuticals, Borough Road, Godalming, Surrey, GU7 2AB, UK. References1 Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001; 44(Suppl 1): S28-S38.2 Wellington K, Jarvis B. Topical pimecrolimus: a review of its clinical potential in the management of atopic dermatitis. Drugs 2002; 62: 817-40. 3 Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, Bush C, Graeber M. Safety and efficacy of pimecrolimus (ASM 981) cream 1 0n the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002; 46: 495-504. 4 Leung DY, Bieber T. Atopic dermatitis. Lancet 2003; 361: 151-60. 5 Larsen FS, Hanifin JM. Epidemiology of atopic dermatitis. Immunol Allergy Clinics NA 2002; 22: 1-24. 6 Leung DY, Hanifin J, Charlesworth EN, Li JT, Bernstein IL, Berger WE, Blessing-Moor J, FIneman S, Lee FE, Nicklas RA, et al. Disease management of atopic dermatitis: a practice parameter. Ann Allergy Asthma Immunol 1997; 79: 197-211. 7 Primary Care Dermatology Society & British Association of Dermatologists. Guidelines for the management of atopic eczema. British Association of Dermatologists, 2003. 8 Hoare C, Li WP, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000; 4: 1-191. 9 British National Formulary. Preparations for eczema. 2004; Section 13.5.1. 10 Kang S, Lucky AW, Pariser D, Lawrence I, Hanifin J, the Tacrolimus Ointment Study Group. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 2001; 44(Suppl 1): S58-S64. 11 Manuskiatti W, Maibach HI. Hyaluronic acid and skin: wound healing and aging. Int J Dermatol 1996; 35: 539-44. 12 Galzigna L. YS795 enzymatic inihbiting and biochemical acitivity. Riv Tub Mal Resp 1992; 2: 2-6. 13 Maffei FR, Carini M, Aldini G, Bombardelli E, Morazzoni P, Morelli R. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective action. Arzneimittelforschung 1994; 44: 592-601. 14 Chandler RF. Glycyrrhiza glabra. In: De Smet PAGM, Keller K, Hänsel R, Chandler RF, eds. Adverse effects of herbal drugs. Berlin: Springer-Verlag, 1997; Chapter 3. 15 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980(Suppl 92): 44-7. 16 Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1989; 144: 13-4. 17 Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001; 10: 11-8. 18 Wilcoxon F. Individual comparisons by ranking methods. Biometrics 1945; 1: 80-3. 19 Breslow N, Day N. The analysis of case-control studies. Lyon, France. 1980. 20 Whalley D, Huels J, McKenna SP, Van Assche D. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents’ quality of life in the treatment of pediatric atopic dermatitis. Pediatrics 2002; 110: 1133-6. 21 Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takaoka R, Folster-Holst R, Potter P, Marshall K, Thurston M, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1 0n the treatment of atopic dermatitis in infants. J Pediatr 2003; 142: 155-62. 22 Reitamo S, Wollenberg A, Schopf E, Perrot JL, Marks R, Ruzicka T, Christophers E, Kapp A, Lahfa M, Rubins A, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 2000; 136: 999-1006. 23 Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, Leung DY, Hanifin JM. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998; 102: 637-44. 24 Coleman PJ. Evidence for a role of hyaluronan in the spacing of fibrils within collagen bundles in rabbit synovium. Biochim Biophys Acta 2002; 1571: 173-82. 25 Abatangelo G, Martelli M, Vecchia P. Healing of hyaluronic acid-enriched wounds: histological observations. J Surg Res 1983; 35: 410-6. 26 Protective effects of procyanidines from Vitis Vitifera seeds on UV-induced photodamage. Proceedings “19th IFSCC Congress”, 1996. 27 Zafirov D, Bredy-Dobreva G, Litchev V, Papasova M. Antiexudative and capillaritonic effects of procyanidines isolated from grape seeds (V. Vinifera). Acta Physiol Pharmacol Bulg 1990; 16: 50-4. 28 Morazzoni P, Bombardelli E. Phytochemical antioxidants for cosmetic applications. Int J Green Chemistry 1995. 29 Calsini P. In vitro effects of telmestein on scavenger pathway of alveolar macrophages and peripheral blood monocytes. Riv Tub Malat App Resp 1992; 24: 259-65. |
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