Executive Summary

Publication Details

An overview of the submission details for the drug under review is provided in Table 1.

Table 1. Submitted for Review.

Table 1

Submitted for Review.

Introduction

Plaque psoriasis is a chronic, inflammatory skin disease characterized by the presence of erythematous inflammatory plaques.2,3 The plaques may be itchy or painful and are usually covered by silver, flaking scales. In addition to the overt dermatological symptoms, plaque psoriasis is often associated with psychosocial symptoms that can impact various aspects of social functioning including interpersonal relationships and performance at school or work.3 The estimated number of Canadians living with psoriasis is approximately one million and plaque psoriasis is the most common form, representing approximately 90% of cases.4,5

The severity of psoriasis is classified as mild, moderate, or severe using criteria such as body surface area (BSA) or scores on the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). The Canadian Guidelines for the Management of Plaque Psoriasis provide two definitions for each measure of disease severity: definitions used in clinical trials and definitions for clinical practice.4 In clinical trials, moderate-to-severe psoriasis is defined by a lower limit of 10% BSA and the same limits have been used to define severe psoriasis.4 The guidelines also highlight that despite the literature available, there is a lack of consensus regarding how disease severity should be defined. This was affirmed by the clinical expert on this review.

In patients with plaque psoriasis, topical agents (such as corticosteroids, vitamin D3 analogues, and retinoids) are the most widely used treatments for the mild form of the disease. Combination therapy may also be considered, which is typically more efficacious than monotherapy.4 The Canadian guidelines define moderate-to-severe psoriasis, clinically, by the inability to be controlled by topical therapy; however, it also states that topical agents used to treat mild psoriasis may still be useful adjunct therapy to systemic therapies or phototherapy. According to the clinical expert consulted for this review, if adequate improvement cannot be achieved with topical therapy and/or phototherapy, the systemic therapies such as cyclosporine, methotrexate, or biologic agents are considered.4,6 With a variety of treatments available, the approach to treating plaque psoriasis is heavily patient-centred where the goals of therapy may differ from patient to patient. It is widely accepted that an effective treatment for plaque psoriasis is also one that a patient is willing to work with.4,7,8 The patient-centred approach was aligned with feedback from the clinical expert consulted for this review.

The drug under review, halobetasol propionate (HP) and tazarotene (TAZ) lotion (Duobrii), is a combination product composed of a topical superpotent corticosteroid (0.01% weight by weight [w/w] HP) and a retinoid product (0.045% w/w TAZ).9 In Canada, HP/TAZ is indicated for improving the signs and symptoms of plaque psoriasis in adult patients with moderate-to-severe plaque psoriasis.9 It is recommended that HP/TAZ is applied in a thin layer to the affected area once a day, and the total dosage should not exceed 50 g per week. If no improvement is seen within 12 weeks of treatment, reassessment of the diagnosis may be necessary.9 The sponsor is requesting that HP/TAZ be reimbursed as per the indication reviewed by CADTH. The objective of this report is to perform a systematic review of the beneficial and harmful effects of 0.01% w/w HP and 0.045% w/w TAZ topical lotion for improving the signs and symptoms of plaque psoriasis in adult patients with moderate-to-severe plaque psoriasis.

Stakeholder Engagement

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from a clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Three patient groups, the Canadian Psoriasis Network (CPN), the Canadian Skin Patient Alliance (CSPA), and the Canadian Association of Psoriasis Patients (CAPP), submitted a coordinated patient input response for the review of HP/TAZ for moderate-to-severe plaque psoriasis. All three patient groups aim to educate and advocate for patients with psoriatic disease and their caregivers with the ultimate goal of improving care and quality of patient life.

Information for this submission was collected through three surveys. First, a survey distributed by CPN which resulted in 61 responses distributed across eight provinces. Second, a survey distributed by CAPP about treatment gaps which resulted in 212 responses distributed across all the provinces. Third, a survey distributed by CPN and CAPP targeting people who had experience with HP/TAZ, which resulted in three responses.

The patient groups describe the experience of living with this chronic disorder, saying that it has a significant impact on their quality of life. Patients also reported feelings of low self-esteem, depression, and avoidance of social activities. Challenges with current topical treatments patients experience include side effects, inconvenience, high cost, and loss of effectiveness after prolonged use. Patients who had experience with HP/TAZ therapy remarked that HP/TAZ manages their itching and appearance of plaques better than previous treatments.

The outcomes patients expect from a new treatment are improved efficacy in terms of resolution of plaques, itching, redness, burning sensation, bleeding, joint pain, general pain, and improvement in the emotional toll of the disease such as depression and/or anxiety, and stigma. Moreover, patients expect a treatment which addresses all their symptoms or is curative.

Clinician Input

The clinical expert consulted by CADTH identified needs in topical therapy for plaque psoriasis that are not being met by the presently available medications in Canada. Adherence is a major issue in topical therapy for plaque psoriasis as patients are unlikely to use medications that leave a visible residue on exposed sites, stain clothing or skin, produce irritation, have an objectionable odour, or are difficult to spread onto plaques. They noted that using multiple topical agents improves efficacy, and that it is preferred as a combination preparation to enhance ease of use and adherence. An ideal treatment in plaque psoriasis would produce a sustained PASI 100 response or DLQI of zero in all patients with little or no risk of adverse effects. This treatment would be easily accessed by the patient and convenient to administer.

According to the clinical expert, HP/TAZ is an appropriate first choice of topical therapy for patients with relatively limited areas of psoriatic involvement, as the efficacy and safety of HP/TAZ in patients with more than 12% of BSA affected by plaque psoriasis has not been established.9 They also felt it would be an appropriate adjunctive therapy in those patients who require systemic drugs. For use as monotherapy, the expert identified that HP/TAZ would be most suitable in patients with relatively limited areas of psoriasis, as the 50 g per week limitation would exclude use in patients with large areas of involvement. Further, they thought it would be challenging to identify patients who are more likely to exhibit a treatment response with HP/TAZ, but would expect those who have clearly documented lack of response to superpotent corticosteroids to do less well.

The clinical expert did not think it would be appropriate to recommend that patients try other treatments before initiating treatment with HP/TAZ. In clinical practice, the clinical expert felt that an informal combination of the view of the prescriber and the patient regarding improvement in the signs of psoriasis and area of involvement at four to eight weeks is most likely to be recorded in an assessment of treatment response. Three reasons that would influence treatment discontinuation were also identified, which included: lack of adequate disease response; presence of significant skin atrophy, folliculitis, irritation, suspected irritant, or allergic contact dermatitis; and the treatment being cost-prohibitive.

Last, the clinical expert felt that a dermatologist is not required to diagnose, treat, or monitor patients who might receive HP/TAZ. Significant prescribing by family doctors, nurse practitioners, and perhaps by other specialists (e.g., rheumatology and internal medicine) was anticipated.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Two identical sponsor-submitted pivotal trials, Study 301 and Study 302, met the inclusion criteria for the systematic review. The two trials were multi-centre, double-blind, randomized, parallel-group studies comparing HP/TAZ to vehicle when applied once daily to adult patients with moderate-to-severe plaque psoriasis. To be eligible for inclusion, patients needed to have an area of plaque psoriasis that was appropriate for topical treatment and covered a BSA of between 3% and 12% (inclusive). Patients were also required to have a clinical diagnosis of psoriasis at baseline with an Investigator’s Global Assessment (IGA) score of 3 or 4. Patients were excluded if they had received prior treatment for plaque psoriasis and failed to respond, or if they received treatment for psoriasis within a specified amount of time. Additional details of the inclusion and exclusion criteria are available in Table 5.

Overall, 418 patients were included in the two studies. A total of 203 and 215 patients in Study 301 and Study 302, respectively, were randomized in a 2:1 ratio to receive HP/TAZ or vehicle lotion. Patients applied the study drug to the treatment area determined by the investigator once daily for eight weeks; a follow-up visit was scheduled four weeks after treatment cessation. Concomitant medications, including non-medicated cleansers, moisturizers, and sunscreens that were approved by the sponsor, were permitted for use on the treatment areas. In both studies, health-related quality of life (HRQoL) was assessed using the DLQI, skin clearance was assessed using the IGA and BSA affected by psoriasis, and the signs of psoriasis (erythema, plaque elevation, and scaling). Skin clearance and HRQoL are considered outcomes that are important to patients. Treatment adherence and productivity were not included as outcomes.

At baseline, patients were a mean age of 48.8 (standard deviation [SD] = 13.3) and 51.8 (SD = 14.3) years in Study 301 and Study 302, respectively. The majority of patients were male (61.0% to 69.1%) and White (80.1% to 92.6%) in the two studies. Most patients randomized to Study 301 and Study 302 had moderate disease (82.8% and 87.4%, respectively), indicated by an IGA score of three. The rest of the patients in both studies were classified as having severe disease by an IGA score of four. The percent BSA affected by psoriasis was a mean 6.2% (SD = 2.9%) and 5.6% (SD = 2.6%) for patients in Study 301 and Study 302, respectively. Overall, the disease characteristics of patients in both of the pivotal trials were similar between the HP/TAZ and vehicle treatment groups, with a few differences to note. In Study 301, patients randomized to vehicle had ▬▬▬▬▬ than patients receiving HP/TAZ ▬▬▬▬▬. In Study 302, patients randomized to HP/TAZ, the mean (SD) size of the target lesion for treatment was ▬▬▬▬▬, and the erythema signs of psoriasis for the target lesion were ▬▬▬▬▬

Efficacy Results

HRQoL was assessed using the DLQI, which was included as an exploratory outcome in both trials. At the week 8 (end of treatment) study visit, the DLQI score for patients in Study 301 had ▬▬▬▬▬ in the HP/TAZ and vehicle treatment groups, respectively. In Study 302, the mean (SD) change from baseline in the DLQI score was ▬▬▬▬▬ patients in the HP/TAZ and vehicle treatment groups, respectively. In the absence of formal statistical testing, no conclusions can be made about whether DLQI was actually reduced in either group or whether there were any differences in DLQI between the two treatment groups.

Skin clearance was assessed using the IGA score and percentage of BSA affected by plaque psoriasis in both of the pivotal trials. The primary end point was treatment success at week 8, defined by at least a two-grade improvement from baseline in the IGA score in addition to an IGA score of clear or almost clear. In Study 301, 35.8% and 7.0% of patients treated with HP/TAZ and vehicle, respectively, had treatment success at week 8. In Study 302, 45.3% and 12.5% of patients treated with HP/TAZ and vehicle, respectively, had treatment success at week 8. In both trials, the difference between HP/TAZ and vehicle in the proportion of patients achieving treatment success (P < 0.001) was in favour of HP/TAZ. Treatment success based on the IGA was assessed at week 12, 6, 4, and 2 as secondary end points, which were analyzed following a gated sequential testing procedure in that order. The difference between HP/TAZ and vehicle in the proportion of patients with treatment success was in favour of HP/TAZ (P < 0.05) at week 12, 6, and 4 in both studies. A descriptive subgroup analysis of treatment success based on the IGA at week 8, by baseline disease severity, was reported in both trials. None of the patients in the vehicle treatment groups with severe disease based on the IGA at baseline achieved treatment success. The proportion of patients with treatment success at week 8 was numerically greater for the HP/TAZ groups than vehicle for patients with both moderate and severe disease at baseline. The latter is consistent with the primary analysis; however, no firm conclusions can be drawn about any of the subgroups in the absence of formal pre-specified testing. The subgroup analyses are also limited by their sample size, as less than 20% of the overall population in each of the two trials were included in the subgroup analysis of patients with severe disease at baseline.

Productivity and treatment adherence were not evaluated as efficacy outcomes in any of the clinical trials included in the review, but dosing compliance was reported. Based on the intention-to-treat (ITT) population and compliance defined by using between 80% and 120% of the expected applications of the study drug while enrolled in the study, ▬▬▬▬▬ of patients were compliant with the study medication.

Harms Results

The percentage of patients that reported at least one adverse event (AE) up to the week 8 study visit in Study 301 and Study 302 was 36.8% and 35.0% for HP/TAZ groups and 19.4% and 23.3% for vehicle groups, respectively. At week 8, serious AEs were only reported by three (2.3%) patients in the HP/TAZ group in Study 301. No serious adverse events (SAEs) were reported in Study 302. The percentage of patients who stopped treatment due to AEs at week 8 was 7.5% and 5.1% in the HP/TAZ groups of Study 301 and Study 302, respectively, and 6.8% in the vehicle group of Study 302. There were no withdrawals due to adverse events (WDAEs) from the study drug in the vehicle group of Study 301. No deaths were reported in the two pivotal trials.

Of the notable harms included in the CADTH review protocol, pruritus was the most frequently occurring. It was reported among 3% of patients in the HP/TAZ treatment group of both Study 301 and Study 302, and 5.5% of patients in the vehicle treatment group of Study 302; pruritus was not reported in the vehicle group of Study 301. Skin atrophy and folliculitis was also reported and only occurred in the HP/TAZ treatment groups (skin atrophy, 3.0% and 0.7% and folliculitis, 1.5% and 2.2% in Study 301 and Study 302, respectively). In addition, events of burning sensation, skin irritation, and hypersensitivity were reported in both treatment groups in a small percentage of patients (≤ 1.5%). Severe dryness and hypothalamic pituitary adrenal (HPA) axis suppression were also included as notable harms in the CADTH review protocol, but neither occurred in either study.

Table 2. Summary of Key Results From Pivotal and Protocol Selected Studies (ITT Set Unless Otherwise Indicated).

Table 2

Summary of Key Results From Pivotal and Protocol Selected Studies (ITT Set Unless Otherwise Indicated).

Critical Appraisal

The trials included in this review were both double-blind randomized controlled trials (RCTs). Both trials used an acceptable method of randomization and concealment of treatment allocation, and there was no reason to suggest randomization or blinding was compromised. Overall, there were no major differences between the baseline disease characteristics that would have significantly impacted the efficacy results. In terms of prior medication use, the vehicle treatment groups ▬▬▬▬▬. The reason for ▬▬▬▬▬ in the vehicle treatment groups is unknown.

The primary and secondary outcomes in both trials were treatment success, defined as at least a two-grade improvement from baseline in the IGA score and an IGA score of clear or almost clear (0 or 1). No evidence for the validity of the five-point IGA scale, which was used in the two trials, was identified for this review; however, the six-point Physician’s Global Assessment (PGA), which is the same scale as the IGA, but the assessor is a physician rather than investigator, was available. There was evidence of reliability in terms of test-retest data and internal consistency, but the outcome is subjective and has poor inter-rater reliability.12 The limitations of this scale introduce uncertainty to the interpretation of the primary and secondary outcomes, as well as the magnitude of observed treatment response. Also, HRQoL was evaluated using the DLQI, which is a validated disease-specific instrument. Between-group comparisons or formal statistical testing of the DLQI was not performed, therefore the conclusions that can be drawn based on this outcome are limited. An appropriate method was used to handle missing data (imputed using Markov chain Monte Carlo [MCMC]) and secondary outcomes of treatment success by IGA were controlled for multiplicity using a gated sequential testing procedure. Statistical testing was conducted for the improvement in the signs of psoriasis, but multiplicity was not controlled for this outcome. Statistical testing and imputation of missing data were not conducted for the BSA, preventing any conclusions that can be drawn from this data.

The two trials included several limitations regarding the generalizability of the results to the target population identified by the indication and Canadian clinical practice. The information available regarding disease severity of the patients who were included in the two trials may be more representative of Canadian patients with mild-to-moderate disease rather than moderate to severe. The mean percent BSA of patients at baseline in the two trials was between 5.5% and 6.5% for randomized patients, however, patients with a BSA as low as 3% were eligible for inclusion in the study. Definitions of disease severity are described in the Canadian Guidelines for the Management of Plaque Psoriasis, which suggest a BSA of 5% is used as an upper limit for mild disease and a BSA of 10% is used as a lower limit for moderate-to-severe psoriasis.4 However, the definitions of disease severity for psoriasis vary across international guidelines. For example, guidelines published by the American Academy of Dermatology and the National Psoriasis Foundation (US) defined disease severity by BSA involvement with less than 3% BSA considered mild, 3% to 10% BSA considered moderate, and greater than 10% BSA considered severe disease.13,14 The clinical expert consulted by CADTH acknowledged that there is lack of consensus regarding the definition of disease severity, but was of the view that the patient populations in Study 301 and Study 302 were more mild than what would be expected in a population of Canadian patients with moderate-to-severe psoriasis. Further, the evidence reviewed is not aligned with the anticipated use of HP/TAZ in clinical practice. According to the clinical expert consulted by CADTH for this review, it is unlikely that HP/TAZ would be used as monotherapy in patients with moderate-to-severe disease. The clinical expert advised that a more likely use of HP/TAZ in this population would be as an adjunct therapy to systemic treatment; however, evidence of this was not identified. Lastly, there is no direct evidence of HP/TAZ compared to other topical treatments for psoriasis, despite the number of available treatments for this disease area. As such, the comparative effectiveness of HP/TAZ remains uncertain.

Indirect Comparisons

Description of Studies

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Efficacy Results

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Harms Results

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Critical Appraisal

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Other Relevant Evidence

Long-Term Safety Study (Study 303)

Description of Study

Study 303 is a 52-week, multi-centre, single-arm, open-label, long-term safety study conducted in adult patients with moderate-to-severe plaque psoriasis defined by an IGA score of 3 or 4. The study drug, HP/TAZ, was applied once daily for eight weeks and then as needed in four-week treatment cycles, depending on treatment success (defined with an IGA score of 0 or 1), which evaluation every four weeks. This four-week evaluation/treatment cycle could continue for up to one year. In total, 555 patients were entered into the study, with 503 that completing three months of the study, 391 completing six months, and 138 patients completing 12 months. Most participants were White (86%) and male (65.6%) and the mean age was 52 years. With respect to baseline disease characteristics, 86.5% of participants were classified with moderate psoriasis based on an IGA score of 3, and the mean percent BSA affected by psoriasis in all participants was 5.6% (SD = 2.65%). Study 303 was designed to evaluate safety of once daily use of HP/TAZ topical therapy. Study 303 was not designed to assess the efficacy of HP/TAZ. IGA and percentage BSA were evaluated to determine treatment success and need for re-treatment. Descriptive statistics were performed to provide an overview of the efficacy and safety results.

Harms Results

In terms of safety, 57.1% of patients experienced an AE after HP/TAZ administration with the most common AEs falling into the categories of general disorders and administration site conditions (30.7%), and infections and infestations (23.5%). A total of 7.5% of patients withdrew due to AEs, and 90% of the reasons for WDAEs were application site reactions. Overall, there were no deaths, and 18 patients experienced a SAE; however, no SAE was more common in one group than the other. In terms of treatment-emergent local skin reactions of at least grade 3 severity, throughout the entire 12-month study period, the incidence of local skin reactions was 22.2% for itching, 6.9% for dryness, and 9.8% for burning/stinging.

Efficacy Results

Efficacy outcomes in Study 303 were presented with descriptive statistics and were only evaluated to determine the need for a four-week HP/TAZ treatment cycle. By week 8, ▬ of patients had achieved an IGA score equating to clear or almost clear. By week 24 the mean percent BSA affected by psoriasis had ▬▬▬▬▬.

Critical Appraisal

Overall, Study 303 identified long-term safety data that should be considered with extended use of HP/TAZ topical therapy. However, the outcomes are limited by the open-label, single-arm study design, as well as the external validity in terms of generalizability to the Canadian patient population in terms of demographics and disease severity.

Phase II RCT (Study 201)

Description of Study

Study 201 was included to supplement the review of HP/TAZ in terms of providing additional efficacy data on comparisons to monad HP and monad TAZ. Study 201 was a phase II, multi-centre, double-blind, randomized, parallel-group, vehicle-controlled RCT conducted in adult patients with moderate-to-severe plaque psoriasis defined by an IGA score of 3 or 4. Patients were randomized 2:2:2:1 to receive HP/TAZ lotion (n = 59), HP monad (0.01%) lotion (n = 63), TAZ monad (0.045%) lotion (n = 59), or vehicle lotion respectively (n = 31). The assigned study drug was applied topically to the affected area, once daily for eight weeks. Patients were followed up at four weeks post-treatment cessation, at week 12. None of the efficacy end points were designated as primary.

Efficacy Results

The efficacy of HP/TAZ was demonstrated with the proportion of patients which achieved treatment success at week 8, defined as a two-grade improvement from baseline in the IGA score and an IGA score equating to clear or almost clear. At week 8, 52.5% of patients in the HP/TAZ group achieved treatment success based on IGA compared with 33.3% of patients in the monad HP group, 18.6% of patients in the monad TAZ group, and 9.7% of patients in the vehicle group. Related to the psoriasis signs, at week 8, 54.2%, 67.8%, and 64.4% of patients achieved a two-grade improvement in erythema, plaque elevation, and scaling, respectively, in the HP/TAZ group.

Harms Results

In terms of safety, a larger proportion of patients experienced an AE in the HP/TAZ (33.9%) and monad TAZ (46.6%) group when compared to the other groups. The most common AEs within these groups were application site reactions. Five patients reported a SAE and no SAE occurred in more than one patient. A higher percentage of patients discontinued the study drug and/or withdrew from the study prematurely due to AEs in the monad TAZ groups (12.1%) when compared to the other groups.

Critical Appraisal

Key limitations of Study 201 related to internal validity include minor imbalances in baseline demographics and disease characteristics, the disproportionate discontinuation rate, and lack of multiplicity adjustment for efficacy outcomes. The key limitation associated with external validity is generalizability to the Canadian patient population in terms of demographics and disease severity.

Conclusions

Based on the available evidence, HP/TAZ demonstrated efficacy in adult patients with plaque psoriasis in terms of skin clearance based on the IGA. In the two trials included in the CADTH review, the difference between HP/TAZ and vehicle in the proportion of patients achieving treatment success (defined by at least a two-grade improvement from baseline in the IGA score in addition to an IGA score equal to clear or almost clear) at week 8 was statistically significant in favour of HP/TAZ (P < 0.001). HRQoL was identified as an outcome that is important to patients and was measured using the DLQI in both studies; however, no conclusions can be made regarding the effect of HP/TAZ on HRQoL due to the exploratory nature of the outcome and lack of statistical testing. In addition, HP/TAZ does not appear to be associated with any safety signals. Key limitations are the lack of comparative evidence, lack of long-term data, and generalizability of the patient population; of note, the patients included in Study 301 and Study 302 may not be representative of Canadian patients with moderate-to-severe plaque psoriasis.

In the absence of direct evidence, the sponsor submitted a network meta-analysis (NMA) with the purpose of evaluating the relative efficacy of topical therapies approved for the treatment of moderate-to-severe plaque psoriasis in Canada. The results of the NMA suggest that after eight weeks of treatment, both combination therapies (HP/TAZ and betamethasone dipropionate [BD] plus vitamin D analogue [VDA]) were superior to vehicle in achieving treatment success; however, the NMA was performed to examine the relative treatment effect between active topical therapies to vehicle, rather than between active therapies.