Journal of Dermatological Treatment ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20 Matching-adjusted indirect comparison of efficacy outcomes in trials of calcipotriol plus betamethasone dipropionate foam and cream formulations for the treatment of plaque psoriasis Kim A. Papp, Henrik Thoning, Sascha Gerdes, Matteo Megna, Henrik Brandi, Marie Y. Jablonski Bernasconi & Oriol Yélamos To cite this article: Kim A. Papp, Henrik Thoning, Sascha Gerdes, Matteo Megna, Henrik Brandi, Marie Y. Jablonski Bernasconi & Oriol Yélamos (2022) Matching-adjusted indirect comparison of efficacy outcomes in trials of calcipotriol plus betamethasone dipropionate foam and cream formulations for the treatment of plaque psoriasis, Journal of Dermatological Treatment, 33:7, 3005-3013, DOI: 10.1080/09546634.2022.2095330 To link to this article: https://doi.org/10.1080/09546634.2022.2095330 © 2022 The Author(s). Published with View supplementary material license by Taylor & Francis Group, LLC. Published online: 25 Jul 2022. Submit your article to this journal Article views: 1488 View related articles View Crossmark data Citing articles: 2 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijdt20 JOURNAL OF DERMATOLOGICAL TREATMENT 2022, VOL. 33, NO. 7, 3005–3013 https://doi.org/10.1080/09546634.2022.2095330 ARTICLE Matching-adjusted indirect comparison of efficacy outcomes in trials of calcipotriol plus betamethasone dipropionate foam and cream formulations for the treatment of plaque psoriasis Kim A. Pappa,b, Henrik Thoningc, Sascha Gerdesd, Matteo Megnae , Henrik Brandic, Marie Y. Jablonski Bernasconic and Oriol Yelamosf,g a Probity Medical Research, Waterloo, Ontario, Canada; bK Papp Clinical Research, Waterloo, Ontario, Canada; cLEO Pharma, Ballerup, Denmark; dCenter for Inflammatory Skin Diseases, Dept. of Dermatology, Venereology and Allergology, University Medical Center Schleswig-Holstein, Kiel, Germany; eSection of Dermatology, Dept. of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; fDermatology Dept, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Bellaterra, Barcelona; gDermatology Dept, Centro Medico Teknon, Quironsalud, Barcelona ABSTRACT ARTICLE HISTORY Background and objectives: Once-daily, fixed-combination calcipotriol 50 lg/g (Cal) plus betametha- Received 27 May 2022 sone dipropionate 0.5 mg/g (BD) is available in aerosol foam and cream formulations. As no head-to- Accepted 16 June 2022 head data are available, we use a matching-adjusted indirect comparison (MAIC) approach to compare KEYWORDS Cal/BD foam and cream. Psoriasis; calcipotriol; Methods: Anchored and unanchored MAIC analyses were conducted using individual patient data betamethasone dipropio- (IPD) from five Cal/BD foam trials and two trials of Cal/BD cream. Outcomes of interest were the pro- nate; foam portion of patients with Physician’s Global Assessment (PGA) success and the mean reduction in modified Psoriasis Area and Severity Index (mPASI). Results: In the anchored MAIC, patients were more likely to achieve PGA success after 4 weeks of Cal/ BD foam than after 8 weeks of Cal/BD cream and had larger mean improvements in mPASI (p < .01 in EU mPASI analysis). In unanchored analyses, 4 weeks of Cal/BD foam treatment was statistically signifi- cantly more efficacious in inducing PGA success than 8 weeks of Cal/BD cream (p < .01 in five of six comparisons). Mean reductions in mPASI were consistently statistically significantly greater with Cal/ BD foam than with Cal/BD cream. Conclusions: Use of Cal/BD foam consistently shows significantly greater improvements in PGA and mPASI outcomes, compared with Cal/BD cream. Introduction (6,7). The increased efficacy of Cal/BD aerosol foam over gel and ointment formulations appears to relate to the formation of a Plaque psoriasis is a chronic, inflammatory, immune-mediated supersaturated layer of product which allows greater penetra- skin disorder characterized by well-defined red, scaly plaques. tion compared with other formulations (8,9). The symptoms of plaque psoriasis impact patients’ health- Recently, a further Cal/BD formulation, a water-containing related quality of life. Itching and scaling are typically the most distressing symptoms for patients, with many patients experi- cream (WynzoraV R , MC2 Therapeutics), has been approved in encing skin pain or discomfort, while psychosocial effects several regions of the world. Cal/BD cream has been compared including isolation, stigmatization and embarrassment are com- with Cal/BD gel in RCTs (10,11), but no head-to-head data com- mon (1–3). Topical medications (alone or in combination with paring the foam and cream formulations are available. systemic drugs) are the most common treatment for patients Clinically, it is important to understand if there is an efficacy with plaque psoriasis, with multiple agents available. difference between the diverse formulations of Cal/BD in order The addition of the vitamin D derivative calcipotriol has to provide individual patients with the most appropriate treat- been shown to increase the efficacy of topical corticosteroids ment to improve their symptoms and control their disease (top- for plaque psoriasis (4), and fixed-combination calcipotriol ical therapies including Cal/BD can be used both as 50 mg/g (Cal) plus betamethasone dipropionate 0.5 mg/g (BD), monotherapy and, for patients with moderate-to-severe psoria- used once-daily, is a recommended first-line treatment (5). Cal/ sis, in combination with systemic drugs). In the absence of BD is available in multiple formulations. Cal/BD aerosol foam head-to-head trials, alternative comparison methods can be (EnstilarV R , LEO Pharma), available since 2017, has been shown in used to compare therapies (12). Matching-adjusted indirect randomized controlled trials (RCTs) to be statistically significantly comparison (MAIC) is an approach to comparing therapies that more efficacious than the Cal/BD gel and ointment formulations uses individual patient data (IPD) from clinical trials of one CONTACT Kim A. Papp kapapp@probitymedical.com Probity Medical Research, 139 Union Street East, Waterloo, N2J 1C4, Ontario, Canada Supplemental data for this article is available online at https://doi.org/10.1080/09546634.2022.2095330. ß 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 3006 K. A. PAPP ET AL. IPD from Cal/BD foam trials Aggregate data from Cal/BD cream trials Comparable data for Cal/BD foam and Cal/BD cream Apply inclusion/exclusion criteria from Adjusted Cal/BD foam IPD Cal/BD cream trials Weight population to match mean Analyse IPD using methods from Cal/BD baseline characteristics of Cal/BD cream cream trials trial arms Anchored MAIC Cal/BD foam Cal/BD cream MAIC RCT RCT Cal/BD gel Unanchored MAIC Cal/BD foam Cal/BD cream MAIC Figure 1. Schematic of MAIC process. IPD from trials of one intervention is selected and weighted to match the mean population characteristics of a second treatment. After adjustment, trial outcomes can be compared either directly (‘unanchored’) or via a common comparator (‘anchored’). BD, betamethasone dipropi- onate; Cal, calcipotriol; IPD, individual patient data; MAIC, matching-adjusted indirect comparison; RCT, randomized controlled trial. intervention and aggregate data from trials of the second, efficacy of Cal/BD foam and Cal/BD cream in inducing weighting the IPD to align the mean characteristics of the inter- Physician’s Global Assessment (PGA) success and in reducing vention populations (12,13). MAIC can be used either when no modified Psoriasis Area and Severity Index (mPASI). common comparator is available (‘unanchored’) or when the two interventions have been investigated in RCTs with a com- mon comparator arm (‘anchored’; Figure 1) – where possible, Materials and methods anchored comparisons are the preferred approach (12). Efficacy outcomes Previously, MAIC analyses have been used to compare the effi- cacy of Cal/BD foam with that of non-biological systemic treat- The primary efficacy comparison was between Cal/BD foam ments and of halobetasol propionate 0.01%/tazarotene 0.045% results at 4 weeks and Cal/BD cream outcomes at 8 weeks, lotion (14,15). reflecting the licensed treatment durations and indications, as In this study, a MAIC approach was used to compare Cal/BD well as the time points at which the primary endpoints of the foam and Cal/BD cream. The objectives of the analysis were to relevant trials were assessed. Where possible, results were also estimate the efficacy of Cal/BD foam in a population matching compared for both treatments at 4 weeks. Outcomes of interest that of the Cal/BD cream trial using MAIC and to compare the were the proportion of patients with PGA success, defined as a JOURNAL OF DERMATOLOGICAL TREATMENT 3007 A Week 4 Week 8 Week 12 Week 56 Cal/BD foam Follow-up PSO-FAST R Foam vehicle Cal/BD foam Follow-up Foam vehicle LEO90100-35 R Cal/BD ointment Ointment vehicle Cal/BD foam Follow-up LEO90100-7 R Cal foam BD foam Cal/BD foam Follow-up PSO-LONG Cal/BD foam R Open-label Foam vehicle Cal/BD foam Follow-up Foam vehicle PSO-ABLE R Cal/BD gel Gel vehicle Cal/BD cream Follow-up Cal/BD cream R Cream vehicle EU trial R Randomization Cal/BD gel Cal/BD cream Primary Follow-up Cal/BD cream endpoint R Cream vehicle US trial timepoint Cal/BD gel B Trial region Trial Analysis EU US Combined PSO-ABLE Anchored mPASI only PSO-LONG PSO-FAST Unanchored 90100-35 90100-7 = both mPASI and PGA success comparisons can be performed. = no data available for comparison. Figure 2. (A) Comparison of included trials. (B) Summary of available data for MAIC analyses. BD, betamethasone dipropionate; Cal, calcipotriol; MAIC, matching- adjusted indirect comparison. score of 0 (clear) or 1 (almost clear) with an improvement of  analysis are summarized in Figure 2A. For the anchored analysis, 2 points from baseline, and the mean reduction in mPASI. Cal/BD foam IPD were taken from the PSO-ABLE RCT, which was conducted in the USA and the EU and compared Cal/BD foam with Cal/BD gel (6). PSO-ABLE results were compared with the MAIC methods and source data available data from the US and EU trials of Cal/BD cream, in Anchored and unanchored MAIC analyses were conducted as which Cal/BD gel was a comparator (Figure 2A). described by Signorovitch et al. (13,16); the overall MAIC pro- Aggregate data for the Cal/BD cream trials were taken from cess is illustrated in Figure 1. The clinical trials included in the two published papers and the study clinicaltrials.gov records 3008 K. A. PAPP ET AL. Table 1. Baseline characteristics before and after matching – PSO-ABLE vs Cal/BD cream trials (anchored MAIC). PSO-ABLE US subgroup PSO-ABLE EU subgroup Cal/BD cream US trial Cal/BD cream EU trial Variable Baseline characteristics Unweighted Weighted Baseline characteristics Unweighted Weighted Cal/BD foam vs cream N ¼ 342 N ¼ 59 Neff ¼ 52.24 N ¼ 213 N ¼ 103 Neff ¼ 39.45 Age, years (SD) 52.00 (14.4) 50.31 (13.42) 52.00 48.60 (13.70) 56.84 (15.20) 48.60 Sex, % male 59.36 64.41 59.36 63.85 70.87 63.85 Mean BSA, % (SD) 7.30 (6.00) 7.05 (6.13) 7.30 7.80 (6.50) 6.17 (4.05) 7.80 Mean mPASI (SD) 7.30 (3.90) 7.22 (4.74) 7.30 8.00 (3.90) 6.15 (3.33) 8.00 PGA, % Mild 19.88 23.73 19.88 17.84 37.86 17.84 Moderate 80.12 76.27 80.12 82.16 62.14 82.16 Skin type, % I or II 31.29 42.37 31.29 51.64 20.39 51.64 III 30.41 32.20 30.41 36.15 45.63 36.15 IV, V or VI 38.30 25.42 38.30 12.21 33.98 12.21 Cal/BD gel arms N ¼ 337 N ¼ 55 Neff ¼ 45.11 N ¼ 209 N ¼ 114 Neff ¼ 49.52 Age, years (SD) 52.60 (13.70) 55.75 (12.85) 52.60 51.50 (14.80) 53.53 (15.59) 51.50 Sex, % male 65.58 60.00 65.58 54.07 57.89 54.07 Mean BSA, % (SD) 8.40 (7.00) 7.27 (5.81) 8.40 7.80 (6.50) 6.17 (4.46) 7.80 Mean mPASI (SD) 7.70 (4.10) 6.61 (3.28) 7.70 8.00 (3.90) 5.96 (3.01) 8.00 PGA, % Mild 16.91 21.82 16.91 18.18 28.95 18.18 Moderate 83.09 78.18 83.09 81.82 71.05 81.82 Skin type, % I or II 32.34 40.00 32.34 50.24 26.32 50.24 III 33.23 34.55 33.23 36.36 46.49 36.36 IV, V or VI 34.42 25.45 34.42 13.40 27.19 13.40 BD, betamethasone dipropionate; BSA, body surface area; Cal, calcipotriol; MAIC, matching-adjusted indirect comparison; mPASI, modified Psoriasis Area and Severity Index; Neff, effective sample size; PGA, Physician’s Global Assessment. (10,11,17,18). Available data from the Cal/BD cream EU trial were arms were well balanced with the Cal/BD cream treatment arms limited, although pooled US and EU results have been published after matching (Table 1; Supplementary Tables 1 and 2). In the (10); data availability is summarized in Figure 2B. anchored analysis, the effective sample sizes after matching For the unanchored analysis, Cal/BD foam IPD were taken were 88.5% and 82.0% of the original population in the US Cal/ from three US RCTs – PSO-FAST (19), LEO90100–35 (7) and BD foam and Cal/BD gel arms, respectively. By contrast, in the LEO90100–7 (20), and from the 4-week open-label phase of the EU analysis, the corresponding effective sample sizes were PSO-LONG Cal/BD foam trial, which included patients in both 38.3% and 43.4%, suggesting greater differences between trial the USA and the EU (21) (Figure 2). populations in the EU comparison. In the unanchored analyses, Data from the Cal/BD cream trials were rounded to the nearest the effective sample sizes after matching were 74.8–96.5% of integer number of patients. The change in mPASI at week 4 in the the original patient numbers, suggesting substantial overlap Cal/BD cream US trial was read from a graph (11). The standard between the Cal/BD foam and Cal/BD cream treatment arm deviation (SD) for mPASI at week 4 was not available for this trial. populations. Instead, the mPASI SD at week 8 was assumed to apply to the week 4 data and was used for both time points. A sensitivity analysis was conducted by using a week 4 mPASI SD calculated from a weighted Anchored MAIC – PSO-ABLE RCT arms average of week 4 variances across all five US Cal/BD foam arms as In the anchored MAIC, US patients were more likely to achieve an alternative estimate of the SD in the Cal/BD cream US RCT. PGA success after 4 weeks of Cal/BD foam than after 8 weeks of Cal/BD cream, although the confidence intervals were wide and Matching trial populations the difference was not statistically significant (Figure 3). Similar results were seen in the pooled US plus EU analysis at 8 weeks, IPD from the Cal/BD foam trials were selected by applying the inclu- and in the corresponding comparisons with 4 weeks of Cal/ sion criteria from the Cal/BD cream trials. Cal/BD foam trial IPD was BD cream. then adjusted by weighting to match the mean baseline characteris- In the US, EU and pooled EU plus US analyses, patients tics of patients treated with Cal/BD cream. Matched EU and US IPD receiving Cal/BD foam for 4 weeks had larger mean improve- were subsequently pooled for the comparison with the pooled EU ments in mPASI than those treated with Cal/BD cream for and US data for Cal/BD cream. The baseline characteristics matched 8 weeks or 4 weeks (only US data could be compared at were age, sex, Fitzpatrick skin type, percentage of body surface area 4 weeks); the difference between treatments was statistically sig- affected, mPASI and PGA; the prognostic relevance of these charac- nificant in the EU analysis only (p < .01; Figure 4). teristics was confirmed by discussion among the authors. Unanchored MAIC – Cal/BD foam RCT arms Results In the unanchored MAIC of Cal/BD foam RCTs, 4 weeks of Cal/ Baseline characteristics BD foam treatment was statistically significantly more efficacious For each of the MAICs informed by the different Cal/BD foam in inducing PGA success than 8 weeks of Cal/BD cream in two trials, the matched baseline characteristics of the Cal/BD foam of the three comparisons (PSO-FAST and LEO90100-35, both JOURNAL OF DERMATOLOGICAL TREATMENT 3009 Favors cream Favors foam Cream Foam OR (95% CI) p value Week 8 vs. week 4 37.4% vs. 47.1% vs. US 1.89 (0.68–5.25) 0.22 22.9% 20.3% 43.2% vs. 37.4% vs. EU and US 1.55 (0.82–2.92) 0.18 31.9% 20.6% Week 4 vs. week 4 24.3% vs. 47.1% vs. US 1.75 (0.62–4.96) 0.29 12.8% 20.3% 25.2% vs. 37.4% vs. EU and US 1.38 (0.72–2.67) 0.34 15.7% 20.6% 0.1 1 10 OR (95% CI) Figure 3. Odds ratios for achieving PGA success is anchored MAIC of PSO-ABLE versus US and EU RCTs of Cal/BD cream. PGA response rates are for the compara- tors vs Cal/BD gel. BD, betamethasone dipropionate; Cal, calcipotriol; CI, confidence interval; MAIC, matching-adjusted indirect comparison; OR, odds ratio; PGA, Physician’s Global Assessment; RCT, randomized controlled trial. Cal/BD Cal/BD Cal/BD Cal/BD foam, Cal/BD Cal/BD foam, cream, cream, Cal/BD foam, cream, US+EU cream, US subgroup US trial US trial EU subgroup EU trial subgroups US+EU trials Week 4 Week 4 Week 8 Week 4 Week 8 Week 4 Week 8 gel in mean mPASI change from baseline, % Difference between comparator and Cal/BD 0 –5 –4.0 –10 –8.0 –8.2 –11.6 –12.0 –13.0 –15 –15.5 –20 MAIC difference in mPASI, –5.0 –1.4 –11.5 –3.8 vs. Cal/BD foam week 4 (95% CI) (–18.2, 8.2) (–14.6, 11.8) (–20.3, –2.7) (–11.6, 4.0) p = 0.46 p = 0.84 p < 0.01 p = 0.34 Figure 4. Mean change in mPASI in anchored MAIC of PSO-ABLE versus US and EU RCTs of Cal/BD cream. Data shown are the difference in mean mPASI change between the comparators and Cal/BD gel. BD, betamethasone dipropionate; Cal, calcipotriol; CI, confidence interval; MAIC, matching-adjusted indirect comparison; mPASI, modified Psoriasis Area and Severity Index; RCT, randomized controlled trial. p < .01), and numerically more efficacious in the third (p < .01; Figure 5B). Similarly, in the EU analysis and in the pooled (LEO90100-7; Figure 5A). When 4 weeks of Cal/BD foam was analysis of EU and US trial data, 4 weeks of Cal/BD foam use was compared with 4 weeks of Cal/BD cream, Cal/BD foam was stat- associated with a statistically significantly greater likelihood of istically significantly more efficacious in all three analyses achieving PGA success, compared with 8 weeks of treatment with (all p < .01). Cal/BD cream (p < .01). Both analyses found statistically signifi- The mean reduction in mPASI with 4 weeks of Cal/BD foam cantly higher response rates when 4 weeks of Cal/BD foam was treatment was statistically significantly greater than with compared with 4 weeks of Cal/BD cream (both p < .01). 8 weeks of Cal/BD cream use in all three analyses (all p < .01; Patients receiving open-label Cal/BD foam for 4 weeks in the Figure 6A). Similar results were found in the comparison with US cohort in PSO-LONG had statistically significantly greater 4 weeks of Cal/BD cream treatment (all p < .01). improvements in mPASI than those using Cal/BD cream for 8 weeks (p < .01; Figure 6B). Similar results were seen in the comparison with 4 weeks of Cal/BD cream (p < .01). In the EU Unanchored MAIC – PSO-LONG open-label phase analysis and in the pooled analysis of EU and US trial data, In the PSO-LONG MAIC, US patients treated with Cal/BD foam improvements in mPASI were statistically significantly greater were statistically significantly more likely to have PGA success at with 4 weeks of open-label Cal/BD foam than with 8 weeks of week 4, compared with 8 weeks of Cal/BD cream treatment Cal/BD cream (p < .01; Figure 6B). 3010 K. A. PAPP ET AL. p value A Favors cream Favors foam Cream Foam OR (95% CI) Week 8 vs. week 4 – US RCTs PSO-FAST 53.3% 1.90 (1.37–2.63) < 0.01 LEO90100-35 37.4% 52.8% 1.83 (1.18–2.84) < 0.01 LEO90100-7 49.4% 1.63 (0.96–2.79) 0.07 Week 4 vs. week 4 – US RCTs PSO-FAST 53.3% 3.54 (2.50–5.01) < 0.01 LEO90100-35 24.3% 52.8% 3.41 (2.17–5.37) < 0.01 LEO90100-7 49.4% 3.05 (1.76–5.27) < 0.01 0.1 1 10 OR (95% CI) p value B Favors cream Favors foam Cream Foam OR (95% CI) Week 8 vs. week 4 EU 50.7% 85.0% 8.43 (4.47–15.88) < 0.01 US 37.4% 81.0% 8.31 (5.59–12.37) < 0.01 EU and US 43.2% 83.3% 8.32 (6.05–11.43) < 0.01 Week 4 vs. week 4 EU 25.8% 85.0% 24.90 (12.99–47.72) < 0.01 US 24.3% 81.0% 15.52 (10.26–23.47) < 0.01 EU and US 25.2% 83.3% 18.74 (13.46–26.10) < 0.01 0.1 1 10 OR (95% CI) Figure 5. Odds ratios for achieving PGA success in unanchored MAIC of (A) PSO-FAST, LEO90100-35 and LEO90100-7 versus US RCTs of Cal/BD cream, and (B) PSO-LONG versus US and pooled US and EU RCTs of Cal/BD cream. BD, betamethasone dipropionate; Cal, calcipotriol; CI, confidence interval; MAIC, matching- adjusted indirect comparison; OR, odds ratio; PGA, Physician’s Global Assessment; RCT, randomized controlled trial. Discussion and quality of life potentially improving treatment adherence, which plays a key role in the effectiveness of topical therapies; This study used a MAIC approach to compare Cal/BD foam and patients are less likely to remain adherent during an 8-week Cal/BD cream, using IPD from five clinical trials of Cal/BD foam course of treatment, compared with a 4-week course. and publicly available, aggregate data from US and EU trials of The rapid response seen with Cal/BD foam is likely to be a Cal/BD cream. Overall, all comparisons found Cal/BD foam to have reflection of the aerosol foam formulation, which does not crys- greater efficacy than Cal/BD cream in inducing PGA success and improving mPASI; the difference between the treatments was stat- tallize, allowing the rapid evaporation of the propellant and istically significant in the majority of comparisons (Figures 3–6). leaving a supersaturated layer of Cal/BD on the skin; this super- The comparisons between 4 weeks of Cal/BD foam and 8 weeks saturated layer has also been associated with greater penetra- of Cal/BD cream are of particular clinical relevance, as these are tion through thick lesions, compared with gel or ointment the licensed treatment periods for daily use of the two therapies formulations (8,23–25). (in the EU and the UK, patients with a response to 4 weeks of After the matching process, the proportion of patients with treatment with Cal/BD foam can continue with proactive twice- PGA success in the included Cal/BD foam trials was similar to weekly maintenance treatment (22)). The MAIC results suggest the results of the original trial populations (6,7,19–21); this is that 4 weeks of Cal/BD foam treatment is more efficacious in consistent with the high effective sample size in most of the inducing PGA success than 8 weeks of Cal/BD cream, with an even MAICs and suggests that the Cal/BD foam study populations greater difference seen between the two formulations after were not substantially different from those of the Cal/BD cream 4 weeks of each. These findings indicate that, in addition to trials. A numerical difference was observed between the PGA greater efficacy over the treatment period, Cal/BD foam works success rate (but no change in mPASI) at week 4 in the Cal/BD more quickly than the cream. Fast response to treatment is gel arms of the PSO-ABLE RCT (6) and the US trial of Cal/BD important to patients, with rapid improvements in skin symptoms cream (11). The reason for this is unclear, and it may reflect JOURNAL OF DERMATOLOGICAL TREATMENT 3011 A Cal/BD foam, Cal/BD foam, Cal/BD foam, Cal/BD cream, Cal/BD cream, PSO-FAST LEO90100-35 LEO90100-7 US trial US trial Week 4 Week 4 Week 4 Week 4 Week 8 0 Mean mPASI change from baseline, % –10 –20 –30 –40 –50 –51.0 –60 –70 –62.9 –72.5 –71.7 –80 –75.3 MAIC difference in mPASI, –21.5 –20.7 –24.3 vs. Cal/BD cream week 4 (95% CI) (–25.9, –17.2) (–26.3, –15.1) (–30.2, –18.5) p < 0.01 p < 0.01 p < 0.01 MAIC difference in mPASI, −9.6 −8.8 −12.4 vs. Cal/BD cream week 8 (95% CI) (−14.0, −5.3) (−14.4, −3.2) (−18.3, −6.6) p < 0.01 p < 0.01 p < 0.01 B Cal/BD foam, Cal/BD Cal/BD Cal/BD foam, Cal/BD Cal/BD foam, Cal/BD PSO-LONG cream, cream, PSO-LONG cream, PSO-LONG cream, US subgroup US trial US trial EU subgroup EU trial US+EU US+EU trials subgroups Week 4 Week 4 Week 8 Week 4 Week 8 Week 4 Week 8 0 Mean mPASI change from baseline, % –10 –20 –30 –40 –50 –51.0 –60 –70 –62.9 –64.6 –67.5 –80 –73.1 –77.6 –90 –82.1 MAIC difference in mPASI, −22.1 −10.2 −14.6 −13.0 vs. Cal/BD foam week 4 (95% CI) (−26.3, −18.0) (−14.4, −6.1) (−18.5, −10.7) (−15.9, −10.0) p < 0.01 p < 0.01 p < 0.01 p < 0.01 Figure 6. Mean change in mPASI in unanchored MAIC of (A) PSO-FAST, LEO90100-35 and LEO90100-7 versus US RCTs of Cal/BD cream, and (B) PSO-LONG versus US and pooled US and EU RCTs of Cal/BD cream. BD, betamethasone dipropionate; Cal, calcipotriol; CI, confidence interval; MAIC, matching-adjusted indirect com- parison; mPASI, modified Psoriasis Area and Severity Index; RCT, randomized controlled trial. unadjusted differences between the trials. In general, there are MAIC is a useful method for assessing the comparative effi- some differences between PSO-ABLE and the other Cal/BD foam cacy of two treatments using evidence generated in different RCTs (6,7,19–21). In particular, PSO-ABLE had a higher propor- clinical trials in which baseline characteristics and treatment tion of patients with mild psoriasis than the other RCTs, which effect modifiers may differ (12,13,16). The MAIC methodology, may have made PGA success (which for patients with the mild originally described by Signorovitch et al. (13,16), is now used disease requires complete clearance of psoriasis) difficult to widely to assess comparative efficacy. MAIC approaches have achieve (6) – variation between PASI and PGA assessment meth- been used several times to compare therapies for plaque psoria- ods has previously been described for therapies providing near- sis, including comparisons of topical treatments, systemic and complete clearance of psoriasis (26). biological therapies (14,15,27–29). A challenge in conducting 3012 K. A. PAPP ET AL. MAICs is that published aggregate data on relevant baseline Acknowledgments characteristics can sometimes be limited. In general, it would be beneficial if the provision of the detailed baseline characteristics Medical writing support was provided by Symmetron Ltd (London, needed for these types of comparisons became standard prac- UK) and Beacon Medical Communications Ltd (Brighton, UK) in tice when publishing trial results, consistent with the current accordance with Good Publication Practice (GPP3) guidelines, and push toward greater public availability of clinical data. was funded by LEO Pharma (Ballerup, Denmark). This study has several strengths. First, this is the first analysis to compare the efficacy of Cal/BD aerosol foam and cream. Disclosure statement Second, this study includes data from five trials of Cal/BD foam and two trials of Cal/BD cream. Data from individual Cal/BD KP has received honoraria for advisory board, speaker, consult- foam trials were used, rather than pooled data, in order to give ant services, scientific officer and/or steering committees from an overview of inter-trial variability. Third, in the unanchored AbbVie, Akros, Amgen, Bausch Health/Valeant, Boehringer analyses, the reduction in effective sample size when data for Ingelheim, Celgene, Celltrion, Coherus, Eli Lilly, Forbion, the Cal/BD foam treatment arms were adjusted to match the Galderma, Janssen, Kyowa Hakko Kirin, LEO Pharma, Meiji Seika Cal/BD cream arms was small, suggesting that the populations Pharma, Merck (MSD), Merck-Serono, Mitsubishi Pharma, of the phase 3 trials were generally similar. Novartis, Pfizer, Reistone, Sanofi-Aventis/Genzyme, Sandoz, The results of these analyses have some limitations. First, as Takeda, UCB, vTv Therapeutics and Xencor; and has received with all indirect comparisons, there may be some bias due to research grants from AbbVie, Akros, Amgen, Anacor, Arcutis, unobserved differences across the trials, for which it was not Astellas, Avillion, Bausch Health/Valeant, Baxalta, Boehringer possible to adjust. Second, only one trial – PSO-ABLE – could be Ingelheim, Bristol-Myers Squibb, Can-Fite Biopharma, Celgene, used for anchored analysis. Third, the effective sample size in Coherus, Dermavant, Dermira, Dow Pharma, Eli Lilly, Evelo, the PSO-ABLE trial arms after adjustment to match the Cal/BD Galapagos, Galderma, Genentech, Gilead, GSK, Incyte, Janssen, cream population was low, limiting the statistical power of the Kyowa Hakko Kirin, LEO Pharma, Medimmune, Merck (MSD), anchored MAIC; however, the results of the anchored analysis Merck- Serono, Moberg Pharma, Novartis, Pfizer, PRCL Research, were generally consistent with the unanchored comparisons. Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Fourth, the PGA success analysis for 4 weeks of Cal/BD cream in Takeda and UCB. HT, HB and MYJB are employees of LEO the US trial relies on data taken from a graph, while for the cor- Pharma. SG has been an adviser and/or received speakers’ hon- responding mPASI analysis it is necessary to use the week 8 SD. oraria and/or received grants and/or participated in clinical trials The results of the SD sensitivity analysis (data not shown) are of AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, essentially identical to the base-case analysis; however, these Amgen, Anaptys Bio, Argenx BV, AstraZeneca AB, Biogen Idec, results should be treated with some caution. Because the week Bioskin, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, 4 data were not used in the primary efficacy comparison, the Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, potential sensitivity of these results to changes in SD was not Incyte Inc., Janssen-Cilag, Johnson & Johnson, Kymab, LEO explored further. Fifth, the LEO90100-07 trial MAIC is limited by Pharma, Medac, MSD, Neubourg Skin Care GmbH, Novartis, the small sample size and resultant lack of statistical power. Pfizer, Principia Biopharma, Regeneron Pharmaceutical, Sandoz Sixth, the high proportion of patients with PGA success in PSO- Biopharmaceuticals, Sanofi-Aventis, Trevi Therapeutics and UCB LONG may reflect the open-label nature of this trial, thereby Pharma. MM has been an adviser and/or received speakers’ hon- limiting the comparability of these results with the RCT data. oraria for AbbVie, Eli Lilly, Novartis, LEO Pharma, UCB, Janssen, Accordingly, the latter comparison was presented separately. Novartis and Amgen. OY has received speaker honoraria from Finally, this analysis included objective efficacy parameters, with LEO Pharma, Merck (MSD) and Bristol-Myers Squibb; and acted patient-reported outcomes and symptoms data not yet com- as a consultant for Almirall, Isispharma and LEO Pharma. pared between the two therapies. This study has compared the efficacy of treatment with Cal/BD foam or Cal/BD cream over 4 or 8 weeks, but the longer-term com- Funding parative efficacy of, for example, twice-weekly maintenance ther- This study was funded by LEO Pharma. The authors did not apy remains unclear. In the absence of head-to-head studies, a receive honoraria for participating in the study. further MAIC of maintenance treatment outcomes would be bene- ficial. In addition, comparative analyses of safety and of patient- reported outcomes – particularly patient preferences and skin symptoms such as itch and pain – would be clinically useful. ORCID Matteo Megna http://orcid.org/0000-0003-1803-2046 Conclusion In conclusion, the MAIC results demonstrate that the use of Cal/ References BD foam as a once-daily treatment for 4 weeks shows signifi- cantly greater improvements in PGA and mPASI outcomes, com- 1. Ljosaa TM, Rustoen T, Mo €rk C, et al. Skin pain and discom- pared with either 4 weeks or 8 weeks of Cal/BD cream fort in psoriasis: an exploratory study of symptom preva- treatment. These improvements in disease severity were demon- lence and characteristics. 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