TITLE: Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam is Effective, Independent of Body Mass Index and the Extent and Severity of Psoriasis

  ABSTRACT.INTRODUCTION:
Good treatment adherence is important in the effective management of psoriasis and is related to both the frequency of applications and the amount of product used versus the recommended dose. The efficacy and safety of fixed combination calcipotriol 50 μg/g (Cal) and betamethasone 0.5 mg/g as dipropionate (BD) in the treatment of psoriasis is well established; an aerosol foam formulation has been developed to enhance adherence. This subanalysis from the Phase III PSO-FAST study evaluates the amount of Cal/BD foam used during treatment and the association between the extent and severity of baseline disease.

ABSTRACT.METHODS:
Patients (≥18 years) with mild-to-severe body psoriasis were randomized 3:1 to once-daily Cal/BD foam or vehicle. The amount of Cal/BD foam and vehicle used over the 4-week study period was evaluated according to three baseline disease assessments: extent of body surface area (BSA) affected by psoriasis, physician's global assessment of disease severity (PGA) and modified psoriasis area and severity index (mPASI). Treatment success and mPASI75 rates were assessed according to body mass index (BMI) and body weight.

ABSTRACT.RESULTS:
323 patients were randomized to Cal/BD foam and 103 to vehicle. At week 4, the mean total amount of Cal/BD foam used was 120.8 g (n = 293), which was similar to the amount of vehicle used (128.9 g; n = 98). The total amount of Cal/BD foam used at week 4 was greater with increasing BSA and increasing severity of baseline PGA and mPASI. Throughout the study, 93.1% of patients in the Cal/BD foam group and 99.0% of patients in the vehicle group missed ≤10% of treatment applications. Treatment success and mPASI75 rates were generally similar when stratified according to BMI and body weight.

ABSTRACT.CONCLUSIONS:
This subanalysis demonstrates that Cal/BD aerosol foam is used appropriately and is effective for the treatment of psoriasis, independent of BMI and the extent or severity of disease.

ABSTRACT.CLINICAL TRIALS NUMBER:
NCT01866163.

ABSTRACT.FUNDING:
LEO Pharma A/S.

BODY.INTRODUCTION:
Therapeutic guidelines for psoriasis recommend the topical use of corticosteroids and vitamin D3 analogs as first-line treatment, either as separate products (used together) or as a fixed combination treatment [1]. Treatment adherence has been recognized as an important issue in the management of chronic inflammatory skin diseases such as psoriasis [2]. Although many patients can manage their psoriasis with topical therapy alone [1, 3, 4], adherence remains a significant issue. Adherence is related to both the frequency of applications and the amount of product used compared with the recommended dose; a systematic literature review found that the frequency of topical treatment application in randomized controlled trials ranged from 55% to 100%, while patients applied between 35% and 72% of the recommended dose [2]. A number of reasons for poor adherence to topical therapy were identified, including a lack of efficacy, excessive time applying the medication, and poor cosmetic characteristics [2]. Adherence was shown to be greater for once-daily treatment as compared with twice daily [2]. Studies have also shown that the topical vehicle used can impact on adherence [5, 6]; patients generally prefer a vehicle that is simple and fast to apply, quickly absorbed and not greasy [7].  The efficacy and safety of the fixed combination of calcipotriol 50 μg/g (Cal) and betamethasone 0.5 mg/g as dipropionate (BD) has been confirmed in long-term trials [8–11]. The ointment and gel formulations of this fixed combination are established first-line treatments for psoriasis [12]. An aerosol foam formulation of the fixed Cal/BD combination has been developed to enhance adherence and increase the therapeutic options available to patients. Previous Cal/BD aerosol foam studies have shown greater in vitro skin penetration compared with other formulations [13], and a significantly greater anti-psoriatic effect over 4 weeks of treatment than Cal/BD ointment [14, 15], gel [16], and individual active ingredients [17], with a comparable tolerability profile [15–17]. In a large, double-blind, Phase III, 4-week study in patients with psoriasis vulgaris (PSO-FAST [NCT01866163]), treatment with Cal/BD aerosol foam led to significantly greater treatment success rates (53.3% vs. 4.8%; P < 0.001) and lower mean modified psoriasis area and severity index (mPASI; excluding head; 2.0 vs 5.5; P < 0.001) scores compared with aerosol foam vehicle [18].  This subanalysis from the PSO-FAST study evaluates the amount of Cal/BD aerosol foam used during treatment and the association between the extent and severity of baseline disease, in patients with psoriasis.

BODY.METHODS.PATIENTS AND STUDY DESIGN:
Patients eligible for inclusion in the PSO-FAST study were ≥18 years of age with a clinical diagnosis of mild-to-severe body psoriasis. Patients had between 2% and 30% of their body surface area (BSA; i.e., trunk and limbs) affected by the disease, with an mPASI score of ≥2. Full inclusion and exclusion criteria have been reported in Leonardi et al. [18].  PSO-FAST (Cal/BD aerosol foam in PSOriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) was a Phase III, multicenter, double-blind study. Patients were randomized (3:1) to Cal/BD aerosol foam or aerosol foam vehicle once daily for up to 4 weeks.

BODY.METHODS.ASSESSMENTS:
The total amount of Cal/BD foam used by each patient during the 4-week study was determined by calculating the difference between the weight of the cans dispensed and the weight of the returned cans, multiplied by a correction factor of 0.41 to account for the propellant gases. Adherence was assessed by calculating the percentage of missed treatment applications (≤10%, >10–≤20%, >20–≤30%, >30–≤40%, >40–≤50% and >50%), as follows: the number of applications of Cal/BD foam missed for a particular visit interval was divided by the total number of days for the interval, multiplied by 100.  Treatment success was defined as the proportion of patients who were clear or almost clear of disease with at least a two-step improvement at week 4, according to the physician's global assessment of disease severity (PGA). The rate of treatment success was the primary endpoint of the study and the data have been reported in Leonardi et al. [18].

BODY.METHODS.ANALYSIS:
The total amount of Cal/BD foam used during the study was evaluated according to three baseline disease assessments: the extent to which a patient's BSA was affected by psoriasis vulgaris; PGA; and mPASI. The proportion of patients achieving treatment success was stratified according to body weight and body mass index (BMI).

BODY.METHODS.COMPLIANCE WITH ETHICS GUIDELINES:
The institutional review boards of all investigational sites approved the protocol. This study was conducted according to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki 1964, as revised in 2013. All patients provided written informed consent prior to enrollment. The ClinicalTrials.gov identifier is NCT01866163.

BODY.RESULTS:
In total, 323 patients were randomized to Cal/BD foam and 103 to vehicle; 313 (96.9%) and 99 (96.1%) patients, respectively, completed the study. Of the 14 patients who withdrew, eight were lost to follow-up.  The overall mean (±standard deviation) total amount of Cal/BD aerosol foam used after 4 weeks was 120.8 ± 85.7 g (n = 293/323), which was similar to the mean total amount of aerosol foam vehicle used (128.9 ± 92.9 g; n = 98/103). The mean amount of drug used per week was also similar between treatment groups: Cal/BD aerosol foam 29.8 g/week, vehicle 32.1 g/week. The mean amount of Cal/BD aerosol foam used was consistent from baseline to week 1 (29.9 g/week), from week 1 to week 2 (28.5 g/week), and from week 2 to week 4 (30.2 g/week).  The total amount of Cal/BD aerosol foam used at week 4 was greater with increasing BSA and increasing severity of baseline PGA and mPASI (Fig. 1a–c). Most patients enrolled in the PSO-FAST study had ≤10% of their BSA involved at baseline (n = 227), and used on average between 88.3 and 117.6 g of Cal/BD aerosol foam during treatment (Fig. 1a). Throughout the 4-week treatment period, 93.1% of patients in the Cal/BD aerosol foam group and 99.0% of patients in the vehicle group missed ≤10% of treatment applications.Fig. 1Mean total amount of Cal/BD aerosol foam used at week 4 by baseline a BSA; b PGA; and c mPASI. BD betamethasone 0.5 mg/g as dipropionate, BSA body surface area, Cal calcipotriol 50 μg/g, mPASI modified psoriasis area and severity index, PGA physician's global assessment of disease severity, SD standard deviation
  Treatment success rates were generally similar irrespective of body weight and BMI (Fig. 2a, b). Similarly, additional evaluation of mPASI75 rates (i.e., the proportion of patients who achieved a 75% decrease in mPASI) did not demonstrate a difference in response according body weight or BMI (data not shown).Fig. 2Treatment success (defined as the proportion of patients who were clear or almost clear of disease with at least a two-step improvement at week 4, according to PGA) rates by a body weight and b BMI. BMI body mass index, PGA physician's global assessment of disease severity, SE standard error


BODY.DISCUSSION:
In the Phase III PSO-FAST study, most patients had mild-to-moderate disease severity (BSA <10%) and, on average, used 88–118 g of Cal/BD foam. The amount of Cal/BD aerosol foam used was comparable to vehicle and the product was used consistently throughout the 4-week study, suggesting that treatment persistence with the foam was good. In addition, patients used an appropriate amount of Cal/BD aerosol foam for the extent and severity of their psoriasis at baseline, since the mean total amount of Cal/BD aerosol foam used increased with increasing baseline BSA, PGA and mPASI.  The primary analysis demonstrated that significantly more patients using Cal/BD foam achieved treatment success versus vehicle and mean mPASI score was significantly lower for patients using Cal/BD foam than vehicle at week 4 [18]. This subanalysis shows that the effectiveness of Cal/BD aerosol foam, based on treatment success rates, was not affected by body weight or BMI, so can be used in all patients irrespective of their size or extent of their BSA that is covered with plaques (as long as it is within the approved label). It has previously been suggested that BMI may be a prognostic factor for the response to treatment in psoriasis [19]; indeed, a number of studies have shown that some biologic therapies are less effective in patients with a BMI ≥25–30 compared with a BMI <25 [19–23].  One limitation of this analysis is that the regular monitoring that occurred during this clinical study of relatively short duration may reinforce patient adherence compared with that observed in the real world. Outside of the clinical trial setting, some patients are unintentionally non-adherent with treatment (e.g., because they forget to use the medication as directed), whilst others are intentionally non-adherent (e.g., altering or stopping treatment because of perceived ineffectiveness or side effects) [24].

BODY.CONCLUSION:
In conclusion, this subanalysis from the PSO-FAST study demonstrates that Cal/BD aerosol foam is used appropriately and is effective for the treatment of psoriasis, independent of BMI and the extent or severity of disease.

Question: Compared to Vehicle  what was the result of Calcipotriol + betamethasone dipropionate  on Mean amount of drug used per week?
Evidence: The mean amount of drug used per week was also similar between treatment groups: Cal/BD aerosol foam 29.8 g/week, vehicle 32.1 g/week.
Answer: no significant difference