Abstract
Background: The fixed-dose combination foam formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) has demonstrated efficacy and a favorable safety profile for the treatment of plaque psoriasis. Recently, a topical lotion of the combination of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) was approved for treating adult plaque psoriasis. Currently, no head-to-head studies have compared Cal/BD foam with HP/TAZ lotion.
Objective: Compare the effectiveness and drug incremental cost per responder (ICPR) of Cal/BD foam vs. HP/TAZ lotion in moderate-to-severe plaque psoriasis.
Methods: An anchor-based, matching-adjusted indirect comparison was conducted for PGA treatment success (Physician’s Global Assessment of “clear” or “almost clear,” [PGA 0/1] with at least a 2-point improvement) using individual patient data from 3 randomized clinical studies of Cal/BD foam and published data from 2 randomized, Phase 3 clinical studies of HP/TAZ lotion. The number needed to treat and ICPR were also calculated.
Results: After reweighting of patients in the Cal/BD foam studies to match summary baseline characteristics of the HP/TAZ lotion study patients and anchoring to vehicle effect, 4 weeks of Cal/BD foam produced a significantly greater rate of treatment success than 8 weeks of HP/TAZ lotion treatment (51.4 vs. 30.7%; treatment difference = 20.7%, p < .001). The number needed to treat with Cal/BD foam was also less than HP/TAZ lotion (1.9 vs. 3.3). Using US wholesale acquisition costs and equal weekly consumption rates, the incremental cost per PGA 0/1 responder relative to vehicle for Cal/BD foam was $3,988 and was 37% lower compared with HP/TAZ lotion ($6,294).
Conclusions: The indirect comparison analyses showed that Cal/BD foam was associated with a greater rate of treatment success, lower ICPR, and quicker treatment response than HP/TAZ lotion in adult patients with moderate-to-severe plaque psoriasis.
Introduction
Psoriasis is a common, chronic inflammatory multisystem disease that affects millions of people worldwideCitation1. In the United States, more than 7 million adults are estimated to be living with the diseaseCitation2. The hallmark of psoriasis is the manifestation of scaling and erythematous plaques that can be disfiguring and are oftentimes painful or severely pruriticCitation1. In many patients, particularly those with severe disease, the effect of the psoriasis on their physical, social, and psychosocial well-being, as well as their quality of life, can be deleterious and, in some, as decompensating as that found in other severe chronic diseases, even cancerCitation3,Citation4. The economic burden of psoriasis is also substantial, contributing to increased health care costs and decreased work productivity and incomeCitation5–7.
There is no cure for psoriasis at this time, with the main goals of treatment being to achieve clearance of skin symptoms and improve the patient’s quality of lifeCitation8. Topical medications are an essential part of the therapeutic armamentarium, either as the mainstay for mild and moderate psoriasis or as a key adjunctive treatment for patients with more extensive diseaseCitation4,Citation9. Topical corticosteroids, such as betamethasone, halobetasol, and clobetasol, are a cornerstone of treatment and have demonstrated effectiveness in treating plaque psoriasis, including patients with moderate-to-severe diseaseCitation10. However, due to potential side effects that can limit their use, corticosteroids are often used short-term and in combination with other topical agents, such as vitamin D3 analogues and retinoids, in a steroid-sparing fashionCitation9.
The combination of a corticosteroid plus vitamin D3 analogue (e.g. calcipotriene) has shown enhanced effectiveness along with minimized toxicity from the corticosteroid-sparing attribute, and is a treatment regimen recommended by the American Academy of Dermatology guidelinesCitation4,Citation9,Citation11,Citation12. The fixed-dose combination formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam, in particular, has demonstrated efficacy and a favorable safety profile in several large randomized clinical studies for patients of all disease severityCitation13–18. The approval of Cal/BD foam in the treatment of plaque psoriasis in patients 18 years or older was based on 2 randomized, double-blind clinical trialsCitation19. The first was a Phase 3 study that demonstrated a higher treatment success rate of 53.3% with Cal/BD foam vs. 4.8% with vehicle foam (p < .001) at 4 weeks. Treatment success was defined as “clear” or “almost clear” skin in patients with moderate-to-severe disease and “clear” skin in patients with mild disease, according to the Physician’s Global Assessment (PGA, also known as the Investigator’s Global Assessment [IGA])Citation18. The second was a Phase 2 study that demonstrated a higher rate of treatment success with Cal/BD foam vs. betamethasone dipropionate or calcipotriene foam (45.0 vs. 30.7%, p = .047; 45.0 vs. 14.9%, p < .001; respectively) at week 4Citation13. Cal/BD foam was considered generally well-tolerated across the 2 studiesCitation13,Citation18.
Like vitamin D3 analogues, topical retinoids, such as tazarotene, can also be used in a steroid-sparing regimen, and previous studies of combination with corticosteroids such as clobetasol and mometasone have demonstrated effectiveness and a favorable safety profile in the treatment of plaque psoriasisCitation20–22. More recently, a once-daily regimen of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) lotion was approved by the FDA for the topical treatment of plaque psoriasis in adultsCitation23. Safety and efficacy of HP/TAZ were assessed in 2 prospective, randomized, double-blind clinical studiesCitation23–25. Specifically, HP/TAZ achieved higher treatment success rates, defined as “clear” or “almost clear” skin and at least a 2-grade improvement in PGA score, than vehicle across both studies (Study 1, 36 vs. 7%, p < .001; Study 2, 45 vs. 13%, p < .001)Citation23–25. HP/TAZ lotion was considered safe and well-tolerated over 8 weeksCitation23–25. While the plethora of treatment options are encouraging for physicians and patients, the paucity of head-to-head comparative studies can hinder evidence-based medicine, particularly making informed choices on the appropriate treatment options in patient care.
In the absence of a head-to-head comparative study, indirect comparisons that are conducted according to rigorous methodology and with careful adjustments to reduce cross-trial differences, may provide a means of interpreting comparative data across individual studies. Such information could help guide treatment and reimbursement decisions. Matching-adjusted indirect comparison (MAIC) is a comparative approach that reweights patients from clinical studies with individual patient data (IPD) such that they match the baseline characteristics of the patients in the study (or studies) with that of the comparator of interest. This approach takes into account the between-trial differences in baseline characteristics, is robust across effect measures, and enables alignment of study outcome definitions as well as comparison of clinically relevant dosesCitation26,Citation27. Indeed, MAIC analyses might offer the best evidence based on a randomized, controlled trial (RCT) that is possible without a head-to-head study; MAIC analyses have previously been conducted for plaque psoriasis and psoriatic arthritis, as well as for other diseasesCitation28–34.
For the two aforementioned combination regimens, Cal/BD foam and HP/TAZ lotion, no head-to-head RCT has been conducted to date. From the respective randomized, large, well-controlled Phase 3 studies, treatment success with an 8-week, once-daily regimen of HP/TAZ lotion appeared to be lower than that of a 4-week, once-daily regimen of Cal/BD foam (40.6% [pooled from the two Phase 3 studies] and 53.3%, respectively); however, conclusions on their relative effectiveness cannot be made due to inherent differences between the studiesCitation18,Citation25. Thus, the MAIC approach was utilized in this study to compare the effectiveness of a 4-week, once-daily regimen of Cal/BD foam with an 8-week, once-daily regimen of HP/TAZ lotion in moderate-to-severe plaque psoriasis, based on pooled IPD from the studies of Cal/BD foam vs. aggregate-level data from the studies of HP/TAZ lotion. Pharmacoeconomic analysis was also conducted to evaluate the cost-effectiveness of the two treatments.
Methods
Selection of studies and parameters for analysis
For Cal/BD foam, three randomized, controlled clinical studies with a vehicle arm (Phase 3: NCT01866163 and NCT02132936; Phase 2: NCT01536886) were included in the comparative analysis as pooled dataCitation16–18. For HP/TAZ lotion, a systematic review of the literature identified two multicenter, randomized, double-blind, vehicle-controlled Phase 3 studies that met the inclusion criteria (NCT02462070, NCT02462122) and were included in the comparative analysis as pooled dataCitation24,Citation25. The details of the different clinical studies are shown in .
Figure 1. Trial designs for Cal/BD foam studies (NCT02132936, NCT01866136, NCT01536886) and HP/TAZ lotion (NCT02462070, NCT02462122). Abbreviations. Cal/BD, calcipotriene plus betamethasone dipropionate; HP/TAZ, halobetasol plus tazarotene; MAIC, matching-adjusted indirect comparison; R, randomization.
This was an anchored MAIC of Cal/BD foam and HP/TAZ lotion in patients with moderate-to-severe plaque psoriasis, as previously described by Signorovitch and colleaguesCitation26,Citation27. Comparative studies were excluded for the following reasons: the sample size included fewer than 40 patients (this exclusion was stipulated to preserve adequate statistical power); treatment efficacy was not measured, or time points of efficacy measurements were not specified; baseline characteristics were not reported; and the mean baseline Psoriasis Area and Severity Index (PASI) score or body surface area (BSA) was greater than 15 (suitable range was 3-15). The latter was defined to remain aligned with recent clinical study standards and ensure sufficient overlap with the mean PASI score of 7.3 from pooled Cal/BD foam trial populations. The studies for Cal/BD foam and HP/TAZ lotion were generally aligned on the fundamental methodologies, including inclusion/exclusion criteria and principal outcomes; however, some inherent differences were systematically considered in the analysisCitation16–18,Citation24,Citation25. To control for potential differences between the patient populations from the different studies, the patients of the Cal/BD foam clinical studies (IPD) were weighted so that their baseline demographics and disease characteristics matched the aggregated study-level data from the HP/TAZ lotion clinical studies (no IPD were available for HP/TAZ lotion studies). Baseline characteristics for matching were selected based on clinical input and by forward selection using a logistic model, with the relevant end point (i.e. treatment success) as the dependent variable and selection entry criteria, p < .2.
The primary end point was similar between Cal/BD foam and HP/TAZ lotion studies, that is, “treatment success” or “controlled disease” defined as the proportion of patients who achieved “clear” or “almost clear” skin (score of 0 or 1), with at least a 2-grade improvement in disease severity, as assessed by a 5-point PGA (or IGA) scaleCitation35. The endpoint definition differed only by the treatment duration (e.g. 4 weeks for Cal/BD foam and 8 weeks for HP/TAZ lotion). Safety assessments were not included in this analysis due to the inconsistency in the reporting of safety data across the included studies.
The HP/TAZ lotion clinical studies imputed missing endpoint values via Markov Chain Monte Carlo multiple imputation. In the absence of more detail on variables used for this approach, missing endpoint values in the Cal/BD studies (IPD) were imputed using the last-observation-carried-forward in the first instance, and as nonresponders as a sensitivity analysis.
Cost per responder and number-needed-to-treat analysis
In the absence of mean treatment utilization data for HP/TAZ lotion, an assumption was made that the mean weekly consumption for HP/TAZ lotion was similar to the mean consumption reported for Cal/BD foam. Drug costs were calculated as the product of the average consumption used throughout the overall treatment period and the wholesale acquisition cost (WAC) per unit dose of Cal/BD foam and HP/TAZ lotion derived from Medi-Span Price Rxi. Number-needed-to-treat (NNT) values represent the number of subjects that need to be treated to ensure 1 additional treatment success (defined as PGA 0/1) vs. vehicle. This was calculated for each of the two treatments as the reciprocal of the difference in success rates compared with vehicle. The estimated incremental cost per responder (ICPR) was calculated by multiplying the NNT by the overall drug costs throughout the treatment period and corresponds to the additional cost to achieve 1 additional responder for each of the treatments vs. vehicle.
Statistical analyses
Individual patient data (IPD) from the pooled Cal/BD foam clinical studies were re-weighted to match the average baseline characteristics of those from the HP/TAZ lotion clinical studies using the Newton-Raphson algorithm (NLPNRA subroutine within the PROC IML). The distribution of weights for each analysis was inspected to check for the presence of any extreme weights. Adjusted proportions and risk differences (Cal/BD foam minus vehicle) were calculated using a weighted multivariate linear regression model; then, indirect comparisons between Cal/BD foam and HP/TAZ lotion were madeCitation36. Sensitivity analyses were conducted by matching for other available baseline characteristics, including PGA score, race, BSA, age, and gender.
Results
Baseline demographics
A total of 848 patients from the three studies with Cal/BD foam (pooled: Cal/BD foam, n = 649; foam vehicle, n = 199)Citation16–18 and 418 patients from studies with HP/TAZ lotion (HP/TAZ lotion, n = 276; foam vehicle, n = 142)Citation25 were included in the MAIC analysis. Across the studies, discontinuation rates were low, ranging from 3.3 to 10.2% for Cal/BD foam studies and 15.8 to 16.7% for HP/TAZ lotion studies.Citation16–18,Citation24,Citation25 The baseline characteristics for potential matching variables are shown in . Overall, the baseline demographics and disease characteristics were comparable across the two HP/TAZ lotion studies. As studies with HP/TAZ lotion did not include patients with mild psoriasis, the proportions of patients with moderate (85.2%) and severe (14.8%) psoriasis (according to the PGA score) appeared to be higher than those in studies with Cal/BD foam (moderate: 71.3%; severe: 9.3%). There was also a higher proportion of White/Caucasian patients in the pooled Cal/BD foam population (89.3%) than in the pooled HP/TAZ lotion population (85.6%).
Table 1. Patient demographics and baseline characteristics before adjusted for matching.
Primary analysis – treatment success
Baseline variables PGA, BSA, sex, and race were identified as significant predictors for treatment success and thus were used for adjusting the baseline-matched populations in the study – pre- and post-reweighting comparisons for treatment success are shown in and . After weighting, Cal/BD foam patients achieved a greater treatment success rate at week 4 than did HP/TAZ lotion patients at week 8 (55.7 vs. 40.6%). In the comparison of active treatment with the respective vehicle, significantly more Cal/BD foam patients achieved treatment success after 4 weeks than did HP/TAZ lotion patients after 8 weeks (51.4 vs. 30.7%; difference = 20.7%; p < .001) (, ). Based on the differences in treatment success compared with vehicle for Cal/BD foam and HP/TAZ lotion, the number needed to treat to achieve 1 additional treatment responder was calculated to be 1.9 with Cal/BD foam and 3.3 with HP/TAZ lotion ().
Figure 2. Matching-adjusted indirect comparison of PGA treatment success for patients treated with 4 weeks of Cal/BD foam or 8 weeks of HP/TAZ lotion. Abbreviations. Cal/BD, calcipotriene plus betamethasone dipropionate; HP/TAZ, halobetasol plus tazarotene.
Table 2. Primary analysis – treatment success (LOCF).
Sensitivity analyses
The comparative effectiveness was reanalyzed with Non-Responder Imputation (NRI) analysis and additional matching for age. Results of the sensitivity analyses are shown in Supplementary Table 1. Specifically, significantly more Cal/BD foam patients achieved treatment success at week 4 than did HP/TAZ lotion patients at week 8 when comparing with their respective vehicle using either NRI analysis (50.9 vs. 30.7%; difference = 20.2%; p < .001) or matching for age (51.2 vs. 30.7%; difference = 20.5%; p < .0001). Overall, the results of the sensitivity analyses consistently favored Cal/BD foam over HP/TAZ lotion.
Incremental cost per responder
The incremental cost of Cal/BD foam for 4 weeks vs. that for HP/TAZ lotion for 8 weeks per responder (defined as treatment success (PGA 0/1)) relative to vehicle is shown in . In the ICPR analysis, equal weekly consumption was assumed in the absence of published consumption rates for HP/TAZ lotion. Overall, for each treatment success compared with vehicle, the use of Cal/BD foam for 4 weeks incurred a 37% lower incremental cost than the use of HP/TAZ lotion for 8 weeks ($3,988 vs. $6,294).
Figure 3. ICPR for patients treated with 4 weeks of Cal/BD foam or 8 weeks of HP/TAZ lotion. Abbreviations. Cal/BD, calcipotriene plus betamethasone dipropionate; HP/TAZ, halobetasol plus tazarotene; ICPR, incremental cost per responder; PGA, Physician’s Global Assessment; WPP, wholesale cost per pack.
Discussion
The favorable efficacy and safety profile of Cal/BD foam in comparison with either its foam vehicle or its gel and ointment counterparts has been demonstrated in several large, randomized, clinical studiesCitation13–18. However, there is limited evidence comparing Cal/BD foam with other topical treatment options, including newer combination medications such as HP/TAZ lotion. Having this evidence can provide valuable information to guide clinical and economic decisions in managing patients with plaque psoriasis. In the absence of head-to-head studies, indirect comparisons of treatment can be conducted via rigorous methodology that carefully adjusts for inherent cross-study differences, in order to reduce biases in the results. One such indirect comparison method, the MAIC, was utilized in the current study to match IPD from three clinical studies of Cal/BD foam with aggregate patient characteristics from two published clinical studies of HP/TAZ lotion to compare treatment success rates and cost-effectiveness for the respective treatments.
Cross-trial differences in baseline characteristics were selectively adjusted, particularly for disease severity (e.g. PGA, BSA), sex, and race, as they were identified to be significant predictors for treatment success. The identification of disease severity was of foremost interest because patients with mild psoriasis (according to PGA) were included in the Cal/BD foam clinical studies but excluded from the HP/TAZ lotion studies. It is possible that the exclusion of mild psoriasis (according to PGA) from the HP/TAZ lotion trials may bias results toward higher effectiveness because treatment success (“clear” or “almost clear” with at least 2 grades improvement) in this patient population, defined as complete clearance, may be more difficult to achieve than in those with moderate-to-severe disease. This is in alignment with the results of this study: MAIC adjustment of baseline characteristics resulted in the exclusion of about 15–30% of patients with mild psoriasis (according to PGA) from the pooled Cal/BD foam population, and, in matching-adjusted populations of moderate-to-severe psoriasis patients, Cal/BD foam produced significantly greater rates of treatment success over HP/TAZ lotion, notably with a shorter duration of treatment (4 vs. 8 weeks, respectively) and better cost-effectiveness ($3,988 vs. $6,294, respectively). The treatment difference remained greater for Cal/BD foam over HP/TAZ lotion when the study populations were further matched for age in the sensitivity analyses. Matching all 4 variables (i.e. overmatching) may potentially lead to a loss of precision in the comparisonCitation37. However, the current MAIC analysis demonstrated statistically significant differences between the two treatments, suggesting that the approach, while conservative, may still provide robust and appropriate comparative analyses.
In addition to this study, two previous studies that used the same methodology have shown that Cal/BD foam had equal or improved effectiveness when compared with 2 systemic agents, apremilast and methotrexate, and was associated with lower costCitation30,Citation38. Even in comparisons of the gel and ointment counterparts of fixed-dose combination Cal/BD formulations, treatment outcome and cost-effectiveness have consistently favored Cal/BD foamCitation16,Citation17,Citation39,Citation40. As expected, use of the Cal/BD foam combination is also more cost-effective than use of each component separatelyCitation41,Citation42.
While this study did not investigate the safety and tolerability of Cal/BD foam and HP/TAZ lotion, their respective safety profiles have been well documented. Based on data derived from 3 prospective vehicle- and/or active-controlled studies, adverse reactions reported in <1% of patients treated with Cal/BD foam included application site irritation, site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasisCitation19. For HP/TAZ lotion, adverse reactions reported in ≥1% of subjects from the randomized clinical studies included contact dermatitis (7%), application site pain (3%), folliculitis (2%), skin atrophy (2%), excoriation (2%), rash (1%), skin abrasion (1%), and skin exfoliation (1%). As with Cal/BD foam, systemic effects of topical corticosteroids include suppression of the hypothalamic-pituitary-adrenal (HPA) axis, with the potential for glucocorticosteroid insufficiency, Cushing’s syndrome, hyperglycemia, and glucosuria. In a study of 20 adult patients with moderate-to-severe plaque psoriasis involving ≥20% of their BSA who were treated with HP/TAZ lotion, incidence of HPA axis suppression at weeks 4 and 8 was 15% and 0%, respectivelyCitation23.
Limitations of the study
There are several limitations to this study that should be considered when interpreting the results. One limitation relates to the presence of unobserved cross-trial differences. While observed cross-trial differences may be reduced or eliminated with MAIC adjustments, unobserved differences may result in residual confounding. For example, there was appreciable difference in treatment success rates between the foam vehicle vs. lotion vehicle, suggesting that vehicle types can potentially influence outcomes, and be potentially compounded by other variables such as differences in patient demographics, adherence, vehicle preference, etc. This limitation can only be avoided with well-controlled head-to-head studiesCitation26,Citation27.
Other differences also exist in the study designs, such as variations in patient population, sample size, randomization scheme for active vs. vehicle group (i.e. randomization to active vs. vehicle arm was 3:1 or 4:1 for Cal/BD foam studies vs. 2:1 for HP/TAZ lotion studies), and treatment duration. Potential inherent differences in the performance of the PGA were also possible. The patient populations differed across studies in terms of the proportion of moderate and severe patients and ethnicities, which may have an inherent impact on the analysis. Regarding treatment duration, 4 weeks of Cal/BD foam was compared with and shown to have a better effectiveness profile than 8 weeks of HP/TAZ lotion. While the treatment durations are in accordance with their respective FDA-approved regimens and/or study primary endpoints, and thus their comparisons may appear to align with real-world clinical use, there is inherent variability associated with different treatment durations that can influence the analysesCitation19,Citation23.
Long-term safety and efficacy studies of topical treatments in psoriasis are needed to further define their role in the treatment armamentarium. In cost analysis, the longer treatment period with HP/TAZ lotion for 8 weeks may inherently translate to greater cost for HP/TAZ lotion than Cal/BD foam for 4 weeks, despite its having a lower cost per pack. The difference in cost may further be compounded by the fact that HP/TAZ lotion had a lower treatment success rate than Cal/BD foam and therefore the incremental CPR remains relatively more expensive than for Cal/BD foam. In addition, the anchored vehicle in studies of Cal/BD (i.e. foam) and HP/TAZ (i.e. lotion) was assumed to be similar (with a cost of zero) and, in the absence of consumption data for HP/TAZ lotion, its weekly consumption was assumed to be equal and similar to that of Cal/BD foam. Finally, the cost input data source and accession date were limited to June 2019, reflecting the recent approval and availability of HP/TAZ lotion in the market. Drug costs in the real-world setting may also differ from the WAC used in this study. Nonetheless, while the MAIC analyses cannot replace an appropriately powered, head-to-head randomized trial, it may still be the best option to provide additional insights into the comparative effectiveness of the drugs in the absence of head-to-head RCTs.
Conclusions
In this MAIC study of Cal/BD foam and HP/TAZ lotion in a patient population with moderate-to-severe psoriasis, Cal/BD foam demonstrated significantly greater treatment success (PGA 0/1) at a lower ICPR than HP/TAZ lotion. The improved treatment success rate, shorter treatment duration, lower number needed to treat, and lower ICPR suggest that Cal/BD foam might offer more of the desired benefits in topical treatment for psoriasis patients. Future direct or indirect comparison, including well-controlled, head-to-head randomized clinical trials, will be important to provide further evidence on the relative treatment effects of these 2 therapies.
Transparency
Declaration of funding
This work was sponsored by LEO Pharma.
Declaration of financial/other interests
Hansen JB, Patel DS, Nyholm N, Veverka KA, and Swensen AR are employees of LEO Pharma. Dr. Wu is or has been an investigator, consultant, or speaker for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dr. Reddy’s Laboratories, Eli Lilly, Janssen, LEO Pharma, Novartis, Regeneron, Sanofi Genzyme, Sun Pharmaceutical, UCB, Valeant Pharmaceuticals North America LLC.
The peer reviewers on this manuscript have received an honorarium from JME for their review work. In addition, a reviewer on this manuscript has disclosed that they have received research, speaking and/or consulting support from a variety of companies including Galderma, SK/Stiefel, Almirall, Alvotech, Leo Pharma, BMS, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Ortho Dermatology, AbbVie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. A second reviewer on this manuscript has disclosed that they have been a consultant and investigator for the manufacturers of both study products and for a number of their competitors. The reviewers have no other relevant financial relationships or otherwise to disclose.
Author contributions
All authors contributed substantively to the study as follows:
Hansen JB conducted the MAIC analyses; Nyholm N conducted the ICPR and NNT analyses; Wu JJ, Patel DS, Veverka KA, and Swensen AR participated in development of the study concept, study execution, and data review. All authors contributed to the development of the manuscript.
Supplemental Material
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p-value communications provided medical writing, editing, and publication assistance and was funded by LEO Pharma.
Note
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