Efficacy
HRQoL was identified as an outcome that is important to patients as noted in the patient input submission for this review, by the clinical expert consulted for this review, and in the clinical practice guidelines4,7 which noted that improved HRQoL is an important outcome for patients that is also a priority in the treatment decision-making process from the clinician perspective. In the two pivotal trials for HP/TAZ, HRQoL was included as an exploratory outcome and measured using the DLQI, which is a well-validated and disease-specific tool. Descriptive analyses were provided, and between-group comparisons were not conducted. After eight weeks of treatment, a reduction in DLQI score was observed in both HP/TAZ and vehicle groups in both studies, which may suggest an improvement in HRQoL. However, in the absence of formal statistical testing, no conclusions can be made as to whether DLQI was actually reduced in either group, or whether there were any differences in DLQI between the two treatment groups.
The primary and secondary outcomes (treatment success based on IGA), and exploratory outcome of BSA affected by psoriasis, in addition to the IGA score by study visit, were reported as outcomes related to skin clearance. In both trials, a statistically significant difference between HP/TAZ and vehicle in terms of the proportion of patients who achieved treatment success based on the IGA was reported at week 8. Similar results were observed at week 12, 6, and 4. Whether the definition used for treatment success is clinically meaningful is unknown as a MID was not identified for the change in IGA score over time, but a score of clear or almost clear is generally accepted as a clinically meaningful score.12 Of note, this was based on the six-point PGA rather than the five-point IGA. A formal assessment of the five-point IGA specifically was not identified during this review. When considering these results, it is important to note the limitations of these analyses, which include the subjective nature and poor inter-rater reliability of the IGA scale,12 and the lack of an active comparator, which introduce uncertainty to the results. The IGA is also not an outcome typically used to assess patients in clinical practice.
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 both patients with 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.
The percentage of BSA affected by psoriasis was an exploratory outcome reported descriptively as a change from baseline. Similar to the DLQI, no between-group comparisons were made, and data were not imputed, limiting the conclusions that can be drawn from this outcome. Nonetheless, the magnitude of the treatment difference was large and the data suggest that the mean (SD) change from baseline in percentage BSA affected was greater in the HP/TAZ groups than vehicle at week 8 in both trials. According to the clinical expert on this review, this outcome is not clinically relevant to Canadian clinical practice.
Improvement in the signs of psoriasis (treatment success, defined as a two-grade improvement in each of erythema, plaque elevation, and scaling) was reported as an exploratory outcome in the two trials. Like the other efficacy outcomes that have been discussed, the proportion of patients that achieved treatment success at week 8 was greater among the HP/TAZ group than the vehicle group. Between-group statistical comparisons were reported for this outcome, which need to be interpreted with increased risk for type I error as the outcome was not adjusted for multiplicity. Evidence of validity, reliability, and responsiveness of the five-point scales used to assess the signs of psoriasis or a MID was not identified for this review. This outcome may be useful for comparison to other clinical trials but lacks clinical relevance. According to the clinical expert consulted for this review, a patient is typically not assessed based on the individual signs of psoriasis in clinical practice. As previously mentioned, signs and symptoms are assessed informally with a focus on how they impact a patient’s HRQoL.
Productivity and treatment adherence were included in the CADTH review protocol; however, these outcomes were not assessed in any of the trials for HP/TAZ. Treatment compliance was reported as a safety outcome, defined by a patient using between 80% and 120% of the expected applications of study drug. By this definition, treatment compliance was high, ranging from ▬ in the two trials, which is not consistent with what is observed in clinical practice. The high rate of adherence observed in the clinical trials likely contributed to an overestimation of treatment effect compared to what would be observed in clinical practice. Nonadherence is a prominent issue in general practice that may impact treatment efficacy, to the point where identifying a treatment that patients are willing to work with is considered alongside identifying a safe and effective option when selecting an appropriate therapy.4,7 The clinical expert consulted for this review noted that in practice patients often discontinue treatment for various reasons, ranging from cost or a lost tube to the fact that the treatment is messy or has an odour. They also noted that the HP/TAZ is a water-based lotion that maybe preferable to patients; however, these types of topical agents are usually more expensive and therefore may not be accessible to many patients.
At the time of this review, there was no direct comparative evidence for HP/TAZ versus other topical treatments for psoriasis. The sponsor submitted an 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 investigated topical therapies included HP/TAZ, high potency corticosteroid/vitamin D analogue combination (BD/VDA), very high potency corticosteroids, retinoids (TAZ), VDAs, and high potency corticosteroids. The results of the NMA suggest that after eight weeks of treatment, both combination therapies (HP/TAZ and BD/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. In addition, the analyses have a number of limitations that impact the internal and external validity creating substantial uncertainty around the results. Therefore, the comparative efficacy and safety of HP/TAZ to other active topical therapies, such as BD/VDA, was inconclusive for the study population due to the limitations in the analyses and substantial uncertainty.
Harms
Overall, AEs were more frequent among patients randomized to HP/TAZ than vehicle. The most commonly reported AE was contact dermatitis, which occurred only in patients randomized to HP/TAZ, and none of the patients who received vehicle in either Study 301 or Study 302. The other AEs reported occurred in no more than five patients per treatment group. Severe adverse events were infrequent and only occurred in the HP/TAZ group of Study 301. No SAE was observed in more than one patient. No deaths were reported, and WDAEs did not appear to be the result of any particular event. A list of notable harms was included in the CADTH systematic review protocol. Of these, pruritus, skin atrophy, folliculitis, burning sensation, skin irritation, and hypersensitivity events were reported. The most frequently reported notable harm was pruritus, which was reported for 2.9% to 5.5% of patients in each treatment group except vehicle of Study 301 (0%). The remaining AEs were reported in five or fewer patients in total. In summary, there are few to no concerns regarding the safety of HP/TAZ based on treatment for eight weeks.
A long-term assessment of safety was conducted in Study 303 and demonstrated safety and tolerability of HP/TAZ intermittent treatment up to one year. During this study, patients discontinued treatment if they achieved treatment success, then reinitiated treatment for a four-week period if disease worsened. Patients were evaluated in four-week cycles for 52 weeks. More than half (57.1%) of patients experienced an AE and 18 (3.3%) patients experienced a SAE. Of the patients who stopped treatment due to AEs (7.5%), most did so due to application site reactions within the first three months. Overall, intermittent treatment with HP/TAZ once daily therapy seemed to be well-tolerated up to 52 weeks. There were no alarming safety signals observed.
The FDA’s review of HP/TAZ was the only regulatory report available at the time of this review. The FDA concluded that a sufficient assessment of safety had been conducted in the target population.42 It is important to note that the indication approved by the FDA is for “for the topical treatment of plaque psoriasis,” which includes a broader patient population than the Health Canada indication. Similar to the discussion of efficacy results, the available safety information for HP/TAZ is limited in its applicability to patients with moderate-to-severe plaque psoriasis, specifically. Moreover, there is a lack of comparative safety data and therefore, safety of HP/TAZ compared to other treatments available for plaque psoriasis is unknown. An assessment of safety was also not included in the sponsor-submitted NMA.
Other Considerations
A topic deserving consideration is that the evidence provided for this review does not align with the anticipated use of HP/TAZ in clinical practice. The clinical expert consulted by CADTH anticipated that HP/TAZ would not be used as a monotherapy in patients with moderate-to-severe psoriasis, and was more likely to be used as an adjunct to phototherapy or systemic therapy (either conventional systemic treatment of biologics). In both Study 301 and Study 302, HP/TAZ was administered as monotherapy and there were no patients in either study who received concomitant treatment with conventional systemic treatment or biologics. This is aligned with the criteria that patients were ineligible for participation in the study if they had used phototherapy, photochemotherapy, or non-biologic systemic psoriasis therapy within four weeks prior to baseline or had used biologics known to affect psoriasis within three months of baseline visit.
According to the clinical expert consulted by CADTH for this review, HP/TAZ is anticipated to be used in patients with mild disease severity, as these patients may be adequately managed on topical therapy. This is aligned with the indication of HP/TAZ approved by the FDA for “the topical treatment of plaque psoriasis,” which is not restricted to patients with moderate-to-severe psoriasis.
