IRCT201205209800N1 IRCT 2012-12-08 ALNAPHARM GmbH & Co.KG Effect of Alnovat in psoriasis A prospective randomized double blinded clinical trial comparing a series of herbal oils (Alnovat) with calcipotriol and vehicle in mild plaque psoriasis 2013-02-19 anticipated 135 Complete https://irct.ir/trial/10330 interventional Randomization: Randomized, Blinding: Double blinded, Placebo: Used, Assignment: Parallel, Purpose: Treatment. 3 Psoriasis vulgaris. Intervention 1: Use of vehicle 2 times per day on all plaques for 12 continuous weeks. Intervention 2: Use of calcipoteriol cream 50mg/g 2 times per day on all plaques for 12 continuous weeks. Intervention 3: Use of Alnovat Cream 2 times per day on all plaques for 12 continuous weeks. Overall, the efficacy analysis demonstrated that Alnovat is not inferior of Calcipotriol and results showed a statistically improved outcome for Alnovat compare to Calcipotriol in reducing PASI score at week 12, which was the primary endpoint for this study. The efficacy was assessed using a pre-specified composite scoring system, the PASI score, which combines the extent of psoriasis with local skin signs (erythema, scale and elevation). This is considered a standard methodology in clinical trials of topical treatments for Psoriasis. Differently from what expected, superiority of Alnovat over Vehicle, originally intended as a placebo cannot be shown. In this study, the Vehicle has shown some activity similar to Alnovat and Calcipotriol, that could be related to its composition (similar to Alnovat). In fact, to ensure blinding, the Vehicle included most of the ingredients of Alnovat (excluding some herbal oils) and most of them have emollient properties. In order to ensure blinding, vehicle included most of the ingredients of Alnovat except for the majority of herbal oils. Just as Alnovat, vehicle contained bitter almond oil which is an antioxidant and, at the same time, has skin moisturizing effects. In addition, vehicle contained middle chain triglycerides, consisting of the saturated fatty acids caproic acid, caprylic acid, capric acid, lauric acid, and myristic acid. Among other lipids, free fatty acids are required for permeability barrier homeostasis in the stratum corneum [34]. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders [35]. Capric acid, lauric acid, and myristic acid are known transdermal penetration enhancers and most of the esters of myristic acid are used as skin conditioning agents in many types of cosmetics in a range of concentrations [1]. Based on this knowledge, a therapeutic effect of the middle chain triglycerides contained in the vehicle cannot be excluded. In summary, there is evidence that vehicle was not a placebo, but a cream with treatment effects on psoriatic lesions. In addition, a subgroup analysis was done to explain the Vehicle effect. For a low degree of disease the “Vehicle effect” was stronger measurable and therefore an added value of Alnovat cannot be detected. But in patients with a stronger degree of disease at baseline, i.e PASI ≥ 3 and PASI ≥4 score points at baseline, the “Vehicle effect” becomes of lower value due to the restricted composition of excipients and treatment with Alnovat was of advantage compared to the Vehicle. The improved reduction in PASI score of Alnovat compared to Calcipotiol remained strong also in this subgroups. Percentage of improvement in PASI scores over time by treatment groups showed that results were comparable with no significant differences at all time points (2 - 4 - 8 - 12 weeks) when Alnovat is compared with Calcipotriol and with Vehicle. This again showed that Alnovat is not inferior of Calcipotriol but is not different from Vehicle. Safety was comparable between treatment group, all reported adverse events were local and patients completely recovered. Eleven patients experienced adverse events: 4 (8.9%) of the 45 patients in the Alnovat group, 4 (8.9%) of the 45 patients in the Calcipotriol group and 3 (6.7%) of the 45 patients in the Vehicle group. All adverse events were considered possibly related and most of the patients with ADE (9/11) discontinued treatment. This double blinded study was conducted in GCP and fully onitored. Carefull drug accountability has been performed showing that all study products have been administered for a similar number of days and in a similar amount of cream. Integrity of data has been ensured by proper data management and statistical procedures.