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Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences.

ABSTRACT: There is increasing use of head-to-head clinical trials in dermatology when establishing the efficacy of a new treatment. Active comparator trials (ACTs) can be classified into three distinct study trial designs: non-inferiority, equivalence and superiority. A better understanding of the statistical parameters, such as acceptable treatment differences (also known as the margin or delta), is necessary to properly design and interpret findings of active comparator trials (ACTs) in the field of dermatology. Therefore, the objective of this study was to summarize the maximum acceptable treatment differences in clinical trials that examine the efficacy of an oral or biologic psoriasis therapy with an active comparator. We conducted a systematic search using MEDLINE, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, LILACS, Web of Science and ClinicalTrials.gov from inception to 31 August 2017. All ACTs with adult participants that had a primary outcome of the Psoriasis Area and Severity Index score were included. Bibliographies of articles were further reviewed. Two investigators independently assessed for article inclusion and separately completed data extraction of predefined data points. When there was a disagreement, a third investigator was consulted. Of the 49 ACTs included, there were 13 superiority, eight non-inferiority and seven equivalence trials. Another 21 studies had inadequate information for classification. All of the non-inferiority trials reported the margin, one of the superiority and six of the equivalence trials stated the treatment difference explicitly. For superiority trials, acceptable treatment differences ranged from 14% to 20%. The non-inferiority studies reported lower bound margins ranging from -20% to -10%. The equivalence trials reported upper and lower bound margins ranging from ±12.5% to ±18%. The results demonstrate the need for harmonization in the conduct of dermatological clinical trials and in the approaches of reporting research parameters.

SUBMITTER: Wan MT

PROVIDER: S-EPMC6328353 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences.

Wan M T MT Alvarez J J Shin D B DB Dommasch E D ED Wu J J JJ Gelfand J M JM

Journal of the European Academy of Dermatology and Venereology : JEADV 20180805 1

There is increasing use of head-to-head clinical trials in dermatology when establishing the efficacy of a new treatment. Active comparator trials (ACTs) can be classified into three distinct study trial designs: non-inferiority, equivalence and superiority. A better understanding of the statistical parameters, such as acceptable treatment differences (also known as the margin or delta), is necessary to properly design and interpret findings of active comparator trials (ACTs) in the field of der ...[more]

PMID: 29989662

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Project description:BACKGROUND:The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized. OBJECTIVES:To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months. METHODS:MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771. RESULTS:Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA. CONCLUSIONS:The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Project description:Oral systemic therapies are important treatment options for patients with moderate-to-severe psoriasis, either as monotherapy or in therapy-recalcitrant cases as combination therapy with phototherapy, other oral systemics or biologics. Long-term treatment is needed to maintain sufficient disease control in psoriasis, but continuous use of systemic treatments is limited by adverse events (AEs) and cumulative toxicity risks. The primary aim of this comprehensive literature review was to examine the long-term safety profiles of oral agents commonly used in the treatment of adults with psoriasis. Searches were conducted in EMBASE and PubMed up to November 2018, and 157 relevant publications were included. Long-term treatment with acitretin could be associated with skeletal toxicity and hepatotoxicity, although evidence for skeletal toxicity is mixed and hepatotoxicity is rare, particularly at low doses. Other safety issues include hyperlipidaemia and potential for teratogenicity up to 2-3 years after discontinuation of treatment. There is a paucity of data on long-term treatment with apremilast. Continued exposure to apremilast does not seem to increase the incidence of common AEs, such as gastrointestinal (GI) AEs, upper respiratory tract infections and headache, while the long-term risks for depression, suicidal thoughts and weight loss are unknown. Long-term ciclosporin treatment is associated with renal toxicity, hypertension, non-melanoma skin cancer, neurological AEs and GI AEs. Long-term methotrexate treatment is associated with hepatotoxicity, GI AEs, haematological toxicity, renal toxicity and alopecia. Finally, long-term treatment with fumaric acid esters (FAE) is associated with GI AEs, flushing, lymphocytopenia, proteinuria and elevated liver enzymes. Median drug survival estimates varied considerably: ~ 2.9-9.7 months for apremilast; ~ 5.4 months for ciclosporin; ~ 8.6 months for acitretin; ~ 12.1-21.6 months for methotrexate; and ~ 54.8 months for FAE. These long-term safety profiles may help to guide clinicians to select the optimal oral systemic treatment for the long-term treatment of psoriasis in adults.

Project description:IntroductionMelasma is an acquired disorder, which presents with well-demarcated, brown-colored hyperpigmented macules, commonly involving the sun-exposed areas such as the face. It is a chronic and distressing condition, affecting the patients' quality of life, and has been conventionally treated with "first-line" agents including hydroquinone (HQ) alone or as a part of a triple combination cream (TCC), while "second-line" options include chemical peels, and third line options include laser therapy.Materials and methodsA systematic search was performed for all topical and systemic treatments for melasma up till May 4, 2021, using the PubMed and EMBASE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The search terms "melasma" and "treatment" were used to search for the relevant articles on both these databases, and a total of 4020 articles were identified. After removing the duplicate entries and screening the titles, abstracts, and full-text articles, we identified 174 randomized controlled trials (RCTs) or controlled clinical trials.ResultsBased on our review, HQ, TCCs, sunscreens, kojic acid (KA), and azelaic acid receive grade A recommendation. Further large-scale studies are required to clearly establish the efficacy of topical vitamin C, resorcinol, and topical tranexamic acid (TXA). Several newer topical agents may play a role only as an add-on or second-line drugs or as maintenance therapy. Oral TXA has a strong recommendation, provided there are no contraindications. Procyanidins, Polypodium leucotomos (PL), and even synbiotics may be taken as adjuncts.DiscussionSeveral newer topical and systemic agents with multimodal mechanisms of action have now become available, and the balance seems to be tipping in favor of these innovative modalities. However, it is worth mentioning that the choice of agent should be individualized and subject to availability in a particular country.

Project description:IntroductionNear-complete skin clearance has become a rapidly achievable treatment goal for patients with psoriasis receiving systemic biologic therapies. However, real-world evidence for durability of near-complete skin clearance and risk factors associated with loss of near-complete skin clearance is limited.MethodsThis study described durability of near-complete skin clearance (≥ 90% improvement in Psoriasis Area and Severity Index from initiation; PASI90) and identified clinical factors or patient characteristics associated with loss of PASI90 among patients with psoriasis from the CorEvitas Psoriasis Registry (April 2015-August 2021). Included patients had PASI > 5 at biologic initiation and achieved PASI90 at approximately 6 months from initiation (index). A Kaplan-Meier estimate described time to loss of treatment response over 24 months follow-up from index. Proportional hazards regression was used to identify independent predictors of loss of treatment response.ResultsThis study included 687 patient initiations (instances of patients initiating a biologic). Following achievement of PASI90, treatment response was maintained in more than half of patient initiations (54%). Treatment response was maintained at 6, 12, and 18 months from index in an estimated 73% (95% [confidence interval] CI 70-77%), 60% (95% CI 56-63%), and 50% (95% CI 47-54%) of patient initiations, respectively. Adjusted hazards regression suggested non-White race, full-time employment, greater body weight, concomitant psoriatic arthritis, prior use of biologics, and clinically meaningful skin symptoms were associated with loss of treatment response.ConclusionsAmong real-world patients with psoriasis who achieved PASI90 with biologic therapy, about one-quarter lost response at 6 months, and half lost response at 18 months. Prior use of a biologic therapy and clinically meaningful skin symptoms at index, including itch and skin pain, were associated with loss of treatment response. Therefore, dermatologists may consider focusing on patient-reported symptoms as part of any intervention designed to reduce the likelihood of loss of response to biologic therapies.Trial registrationClinicalTrials.gov identifier, NCT02707341.

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Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences.

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Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences.

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