A Preliminary, Open Label, Single-arm Study of Calcipotriene/Betamethasone Topical Suspension as a Supplement to Non-biologic Systemic Therapy for Psoriasis

| April 1, 2016
Spread the word.
Email this to someonePrint this pageShare on FacebookTweet about this on TwitterShare on LinkedInShare on Google+Pin on PinterestShare on TumblrBuffer this pageDigg thisFlattr the authorShare on RedditShare on StumbleUponShare on YummlyShare on VK

Laura Korb Ferris, MD, PhD; Erine Kupetsky, DO, MSc; Neil A.M. Houston, BA Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Disclosure: Dr. Ferris is a Principal Investigator for Amgen, Janssen Biotech, Abbvie, Celgene, Pfizer, Novartis, Medimmune, Eli Lilly, LEO Pharmaceuticals, Boehringer Ingelheim, and GSK. Drs. Kupetsky and Houston report no relevant conflicts of interest.


Abstract

Background: Calcipotriene/betamethasone topical suspension is a topical therapy that is often used as monotherapy as a first-line treatment for plaque psoriasis. The objective of this preliminary, open label, single arm study was to determine the efficacy of adding a topical suspension to a traditional systemic therapy for psoriasis, either methotrexate or acitretin. Methods: In this exploratory study, eight patients with chronic plaque psoriasis who were on stable methotrexate or acitretin treatment without clearance were treated with once-daily calcipotriene/betamethasone topical suspension. Subjects completed five study visits over 12 weeks. Primary outcome measure was improvement of two or more points in Investigator Global Assessment. Secondary endpoints included change in Body Surface Area, Dermatology Life Quality Index, and Patient’s Global Assessment from baseline to Week 12. Results: Overall, the median decrease in Investigator Global Assessment over 12 weeks was 1.5 points, with 50 percent of subjects experiencing a drop of two or more points in Investigator Global Assessment. All eight subjects had a reduction in Body Surface Area and Patient’s Global Assessment. There was a mean decrease in Dermatology Life Quality Index score of 78.9 percent, showing improved patient quality of life. In addition, all patients tolerated the treatment well and 6 of 8 patients had improved satisfaction level with their treatment by the end of the study. Conclusion: The topical suspension was effective and well-tolerated in conjunction with stable methotrexate or acitretin treatment in all eight patients in this study. These results support the feasibility of a larger scale study to further investigate the efficacy of these treatment combinations. The trial is registered at ClinicalTrials.gov, number NCT01761019. (J Clin Aesthet Dermatol. 2016;9(4):33–38.)


Psoriasis is a chronic inflammatory skin disease characterized by red, scaly, raised plaques. Plaque psoriasis has a worldwide prevalence of two to three percent, and can profoundly impact a patient’s quality of life, causing physical disability and emotional distress comparable to other major medical diseases, such as type 2 diabetes, hypertension, metabolic syndrome, myocardial infarction, depression, and arthritis.[1]

Many patients with mild disease are able to control psoriasis symptoms with topical medications alone. There are a variety of topical options available, including corticosteroids, synthetic vitamin D3, vitamin A, coal tar, salicylic acid and a number of other products of varying efficacy. The combination topical suspension of calcipotriene 0.005% and betamethasone dipropionate 0.064% is a first-line treatment for moderate-to-severe psoriasis vulgaris and is United States Food and Drug Administration (FDA) approved for use on the skin and scalp in adults 18 years and older.[2] This treatment combines the pharmacological effects of calcipotriene hydrate as a synthetic vitamin D3 analog and betamethasone dipropionate as a synthetic corticosteroid. It is well-tolerated and has a low rate of adverse events according to pooled safety data from 2,700 patients who have used a calcipotriene/betamethasone combination in clinical trials.3 Calcipotriene/betamethasone topical suspension has also been shown to have a positive impact on patient quality of life, as seen in clinical trials utilizing patient-reported outcomes, such as the Dermatology Life Quality Index (DLQI) and Psoriasis Disability Index.[4–6]

Although topical medications can often be an effective treatment for mild disease, patients with moderate-to severe-disease usually require treatment with systemic agents to achieve good clearance. Traditional systemic agents, including methotrexate and acitretin, have a long history of use in the treatment of psoriasis and are used safely and effectively in many patients with psoriasis. Both agents are moderately effective in the treatment of psoriasis with studies showing that 25 to 40 percent of patients will achieve a 75 percent or greater reduction in their psoriasis severity when using one of these agents as monotherapy.[7]

Biologic agents that target specific cytokines involved in the pathogenesis of psoriasis have been a significant advancement in the treatment of moderate-to-severe psoriasis and offer high efficacy. However, the cost of biologic therapy far exceeds that of traditional systemic therapy with a year of therapy costing on average, $1,197 to $1,393 for methotrexate, $9,163 to $21,736 for acitretin, and $24,000 to $48,000 for the most commonly used currently FDA-approved biologics for psoriasis (etanercept, adalimumab, and ustekinumab).[7],[8] Thus, in a patient who requires systemic therapy for psoriasis, it is common to start therapy with either methotrexate or acitretin as these agents are considered to be more cost effective than biologic therapy. Often, these traditional systemic agents are ineffective as monotherapy and patients will then be changed to a biologic agent. Calcipotriene/betamethasone topical suspension is a therapy commonly used to treat patients with mild-to-moderate psoriasis. Currently, there have been no formal trials studying the efficacy of calcipotriene/betamethasone topical suspension used in conjunction with methotrexate or acitretin. In order to better understand the effectiveness of this treatment combination, the authors conducted a preliminary, open label, single arm prospective study to determine the benefit of adding betamethasone-calcipotriene topical suspension to ongoing systemic psoriasis therapy in subjects who do not have complete clearance of psoriasis on a single systemic agent alone. This study was designed to assess the feasibility of a larger-scale study and to better identify outcome potential in order to sufficiently power a larger study with the correct sample size. The rationale for this study is that the addition of the topical suspension could improve psoriasis, from the perspective of both the physician and the subject, reducing the need to switch to another systemic or biologic agent. This could result in significant cost savings, particularly if adding the topical suspension would reduce the need to switch a patient from a traditional systemic agent to a more expensive biologic agent.

METHODS

Patients. Eight subjects ages 38 to 65 years, with stable plaque psoriasis for at least three months prior to enrollment, were included in the study (Table 1  ). Inclusion criteria included Investigator Global Assessment (IGA) of 2 or greater and psoriasis involving a body surface area (BSA) of 2 to 10 percent, as determined by the investigator, and currently taking a stable dose of methotrexate or acitretin for two months prior to enrollment. For inclusion, the methotrexate dose was required to be 7.5 to 25mg per week and the acitretin dose was required to be 10 to 50mg per day. Subjects must not have used phototherapy or topical therapy for 28 days prior to baseline. Subjects were excluded from the study if they had used calcipotriene/ betamethasone topical suspension or calcipotriene/betamethasone ointment at any time in the past or if they were using or had used any other systemic therapy for psoriasis in the three months prior to baseline.

Study design. This study was approved by the University of Pittsburgh Institutional Review Board and all patients gave signed, informed consent prior to enrollment. The study was conducted at the University of Pittsburgh Medical Center (UPMC) Department of Dermatology in Pittsburgh, Pennsylvania, from April 2013 to September 2014.

Subjects completed five study visits over 12 weeks. These included a baseline visit and follow-up visits on Week 2, Week 4, Week 8, and Week 12. The primary outcome of this study was to determine the efficacy of adding the topical suspension to a traditional systemic therapy for psoriasis, either methotrexate or acitretin, as measured by percentage of subjects with an IGA of mild2 or moderate3 or higher at baseline achieving an IGA of 0 (clear) or 1 (almost clear) at Week 12. Secondary objectives included percent of subjects achieving an IGA of 0 or 1 at Weeks 2, 4, and 8, as well as an assessment of change in BSA and DLQI from baseline to Week 12. Subject satisfaction was evaluated by measuring change in satisfaction with current treatment, desire to change systemic therapy at baseline versus 12 weeks, and the results of Patient’s Global Assessment (PGA). PGA established the percentage of subjects who have an improvement of 1 or more points in their assessment of their disease severity using a 6-point scale (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe, 5=very severe).

At each visit, IGA and BSA were evaluated by the physician investigator, subjects completed a PGA to assess their own disease severity, and they were asked about their level of satisfaction with current treatment on a 1 to 4 scale corresponding to 1=“very disappointed”, 2=“somewhat disappointed”, 3=“satisfied”, and 4=“very satisfied”. Patients were also asked at each visit about their desire to change to another systemic therapy. Subjects completed a DLQI only at baseline and Week 12. Eligible subjects self-applied the calcipotriene/ betamethasone topical suspension at the baseline visit during an education session by the investigator. The same application dose was administered once daily for 12 weeks, with subjects instructed not to exceed 100g/week. Subjects were taught to shake the bottle prior to use and apply to affected areas on body or scalp daily while avoiding bathing or showering right after the application. Photographs of a target plaque at baseline and each time point were optional for subjects willing to participate.

Statistical analysis. Primary and secondary endpoints were evaluated by determining mean and individual percent change across study visits, using subjects as their own control pre- and post-intervention. Data for each subject was plotted to determine trends over time. Eight subjects completed all study visits and were included in the data analysis.

RESULTS

In total, all eight subjects completed all study visits. As displayed in Table 1 , five men and three women participated, with the mean age of 51 years and a mean duration of disease of 26.5 years. Four subjects were being treated with a stable dose of methotrexate and four with a stable dose of acitretin. The mean age of patients using acitretin (56.25 years) was nearly 10 years older than the patients using methotrexate (46.5 years), yet the mean duration of disease was nearly identical at 26 versus 26.75 years for acitretin and methotrexate. At the Week 12 visit, seven of eight subjects had achieved an IGA of 1, resulting in 87.5 percent treatment success rate based on the defined criteria (Figure 1). The subject who did not meet an IGA of 0 or 1 at Week 12 had reached an IGA of 1 at Week 4 and regressed back to an IGA of 2 at the following visit. There was a mean reduction in IGA over the 12-week period from 2.75 to 1.125, corresponding to a 59.1-percent improve-ment, with the greatest change being a 3-point reduction in one patient. The median decrease in IGA over 12 weeks was 1.5 points, with 50 percent of subjects experiencing a drop of 2 or more points. At Week 4, five patients had achieved and IGA of 1, and at Week 8, there was a 75 percent treatment success rate with six patients reaching an IGA of 1. After 12 weeks, the mean BSA declined from 2.6 at baseline to 0.7, for a mean improvement of 72.7 percent (Figure 2). Although all subjects showed a reduction in BSA by the end of the study and three subjects reached a BSA of 0.1 percent, none achieved complete clearance by Week 12 (Figure 3). Postinflammatory hyper-pigmentation was noted in one subject at Week 8 after marked plaque reduction to 0.1 percent BSA.

Patient assessments showed a similar trend to the physician assessments. The mean reduction in PGA over the course of the study was 1.875 points, from 3.125 at baseline to 1.25 at Week 12, reflecting a 60 percent mean improvement (Figure 4). The median decrease in PGA over 12 weeks was 2 points, with 62.5 percent of subjects experiencing a drop of 2 or more points. Only one subject had no change in PGA. From baseline to the end of the study, there was also a mean decrease in DLQI from 7.125 to 1.5, corresponding to an improvement of 78.9 percent. The largest improvement was 15 points in one subject and the smallest improvement was 1 point in one subject. In addition, there was a mean improvement in patient satisfaction of 0.875 on a 4-point scale (Figure 2). Two subjects had a decrease in their satisfaction level, while six subjects had improved satisfaction with their current treatment by Week 12. Two subjects desired to change to a different systemic medication at the end of the study, yet both of these subjects noted increased satisfaction with their treatment. There was no change in the number of subjects who desired to change systemic medications from baseline to Week 12.

Considering the use of methotrexate or acitretin with the topical suspension, the group of eight subjects was evenly divided with four patients using each systemic therapy within the dosing guidelines defined in the study inclusion criteria (Table 1  ). Physician assessment of IGA was similar in both the methotrexate and acitretin groups, with a mean reduction of 1.5 points and 1.75 points, respectively. Similarly, patients using methotrexate had a 1.8-percent reduction in BSA compared to a 1.9-percent reduction in the acitretin group. Patient reported outcomes were not as uniform between the two groups; the acitretin patients experienced an improvement in mean PGA of 2.5 (66.7%) and DLQI of 7.5 (88.2%), compared to 1.25 (50%) and 3.75 (65.2%) in the methotrexate group.

The only adverse event reported during the study was an upper respiratory infection in a patient on stable methotrexate therapy. The principal investigator determined that this event was not due to the calcipotriene/betamethasone topical suspension. The topical suspension was well-tolerated by all subjects throughout the study.

DISCUSSION

Calcipotriene/betamethasone topical suspension was shown to provide additional improvement in chronic plaque psoriasis in eight subjects on stable systemic therapy prior to the study. The level of improvement varied among the subjects, but all eight subjects demonstrated improvement in IGA, BSA, and DLQI. Since previous studies showed that topical combination therapy could take effect in a short period of time, IGA and BSA outcomes were evaluated at every study visit.[6],[9],[10] The quick response to treatment was seen in this study; five of eight patients reached a successful treatment outcome at four weeks. Both mean IGA and BSA outcomes improved with each subsequent visit and the largest mean improvement was seen at the end of the study, demonstrating an important trend of improved disease symptoms nearing complete clearance in a number of patients while undergoing no alteration in systemic therapy. This suggests the potential for disease control within acceptable limits and the possibility of transition to maintenance therapy with this topical suspension in some patients.

A major trend seen in our 12-week study was improved treatment satisfaction along with a reduction in perceived disease severity as assessed by the PGA and an improvement in the patient’s quality of life as determined by their DLQI results. This outcome is important to note since improved patient satisfaction and quality of life may prolong patient willingness to continue a systemic therapy that has not achieved full clearance of disease. Overall eight subjects experienced improvement in DLQI despite the possibility that the time needed to apply the topical suspension once daily would create a burden due to the addition of a second treatment. However, this was not the case in our study. The calcipotriene/betamethasone topical suspension is a lipophilic, alcohol-free gel formulation in a pointed tip-delivery bottle that is designed to improve patient satisfaction and adherence.[11] By the end of the study, five patients reported being “very satisfied” with their treatment and three were “satisfied”, whereas only two patients reported being “very satisfied” at baseline, with two patients “satisfied” and four patients “somewhat disappointed” with their treatment. All eight patients planned to continue use of the topical suspension following the study.

The greatest limitation of this exploratory study was the small sample size. Other study limitations include the open label, non-randomized design and absence of a placebo arm.

The combination of systemic therapy and calcipotriene/ betamethasone topical suspension has the potential to more effectively treat psoriasis and improve quality of life, while adding another treatment alternative for patients who are unhappy with the results of systemic monotherapy. Although this study consisted of only eight subjects, the widespread improvement among the subjects sets a precedent for a larger, randomized, placebo-controlled study of subjects on stable systemic therapy for chronic plaque psoriasis. Since treatment options for psoriasis are limited, and patients often must change systemic therapy at some point due to intolerance, lack of response, or dissatisfaction with the treatment result, it is valuable to have additional therapy that can be safely added to a systemic treatment regimen in order to decrease patient symptoms and improve their quality of life. In addition, since patient satisfaction and quality of life related to disease state play a major factor in clinical treatment decisions, the improvement seen in DLQI and satisfaction scores are of significant value and further support the importance of a larger scale study to evaluate the potential of adding calcipotriene/betamethasone topical suspension to systemic therapies.

References

1. Boehncke W-H, Schön MP. Psoriasis. Lancet. 2015:983–994.

2. Taclonex topical suspension, Prescribing Information. Leo Pharma Inc.; 2010. http://www.leo-pharma.us/Files/Billeder/ LEO_local_images/LEO-Pharma.US/Taclonex%20topical suspension%20US%20PI%2011.2010.pdf. Accessed on September 4, 2012.

3. Kragballe K, van de Kerkhof P. Pooled safety analysis of calcipotriol plus betamethasone dipropionate gel for the treatment of psoriasis on the body and scalp. J Eur Acad Dermatol Venereol. 2014;28(Suppl 2):10–21.

4. Menter MA, Caveney SW, Gottschalk RW. Impact of clobetasol propionate 0.05% spray on health-related quality of life in patients with plaque psoriasis. J Drugs Dermatol. 2012;11(11):1348–1354.

5. Sticherling M, Eicke C, Anger T. Practicability of combined treatment with calcipotriol/betamethasone gel (Daivobet® Gel) and improvement of quality of life in patients with psoriasis. J Dtsch Dermatol Ges. 2013;11(5):420–427.

6. Menter A, Gold LS, Bukhalo M, et al. Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial. J Drugs Dermatol. 2013;12(1):92–98.

7. Staidle JP, Dabade TS, Feldman SR. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency. Expert Opin Pharmacother. 2011;12:2041–2054.

8. Brezinski EA, Dhillon JS, Armstrong AW. Economic burden of psoriasis in the United States: a systematic review. JAMA Dermatol. 2015;151(6):651–658.

9. Langley RG, Gupta A, Papp K, et al. Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial. Dermatology. 2011;222(2):148–156.

10. Jemec GB, Ganslandt C, Ortonne JP, et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. J Am Acad Dermatol. 2008;59:455–463.

11. Daudén E, Bewley A, Lambert J, et al. Expert recommendations: the use of the fixed combination calcipotriol and betamethasone dipropionate gel for the topical treatment of psoriasis. J Eur Acad Dermatol Venereol. 2014;28(Suppl 2):22–32.

Spread the word.
Email this to someonePrint this pageShare on FacebookTweet about this on TwitterShare on LinkedInShare on Google+Pin on PinterestShare on TumblrBuffer this pageDigg thisFlattr the authorShare on RedditShare on StumbleUponShare on YummlyShare on VK

Category: General, Original Research

Comments are closed.