Use of Active Comparator Trials for Topical Medications in Dermatology.
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ABSTRACT:
SUBMITTER: Miller J
PROVIDER: S-EPMC8027931 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Use of Active Comparator Trials for Topical Medications in Dermatology.
Miller John J Ly Sophia S Mostaghimi Arash A Barbieri John S JS
JAMA dermatology 20210501 5
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Project description:Clinical trials are the backbone of modern day medicine. Randomized, double-blinded, placebo-controlled studies are critical for advancement in medicine and dermatology. Skin conditions such as psoriasis and atopic dermatitis are among the most common health problems in the United States. Clinical trials can provide treatments that not only offer objective improvements in clinical disease status but also subjective improvements in the quality of life of patients who are afflicted with the disease. In this article, we discuss the processes and resources of a clinical trials unit and the challenges that can be encountered during the study process. It is critical to engage in clinical trials to treat patients most effectively with new and innovative therapies that are rooted in trial-validated, evidence-based medicine.
| S-EPMC5555277 | biostudies-other
Project description:Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.
| S-EPMC6901833 | biostudies-literature
Project description:ImportanceDuring the last decade, increases in drug prices for commonly prescribed dermatologic medications have outpaced the rate of inflation, national health care growth, and reimbursements. Among nondermatologic medications, studies have shown a role for robust generic market competition in reducing drug prices. The association between competition and the costs of topical dermatologic generic drugs has not been evaluated.ObjectiveTo characterize the association between changes in drug price and the number of US Food and Drug Administration (FDA)-approved manufacturers among the most commonly used topical dermatologic generic products.Design, setting, and participantsThis retrospective cost analysis of the most commonly prescribed topical dermatologic generic drugs used cumulative annual claims data from the Medicare Part D Prescriber Public User File to identify 597 dermatologist-prescribed drugs with more than 10 claims. The number of manufacturers and the price per unit were identified from the FDA Orange Book and the National Average Drug Acquisition Cost (NADAC) database, respectively, for 2013 through 2016. Drugs that were nondermatologic, were not topically administered, were missing NADAC data, were lacking a generic formulation, or had fewer than 400 claims were excluded.Main outcomes and measuresPrimary outcomes included per-unit drug price and number of FDA-approved manufacturers. Pricing measures were adjusted for inflation and are reported in 2016 dollars.ResultsThe present analysis included 116 topical dermatologic generic formulations, representing 70.5% of the total Medicare Part D dermatologist-coded claims from 2015. Drug formulations with 1 to 2 manufacturers during the study period sustained a median percentage increase in price of 12.7%, whereas those with more than 6 manufacturers had a median percentage decrease in price of 20.5%. Formulations with 1 to 2 manufacturers had a 20.6%, 19.5%, and 33.2% higher percentage increase in price than those with 3 to 4 manufacturers, 5 to 6 manufacturers, and more than 6 manufacturers, respectively. There was a statistically significant inverse association between the percentage change in drug price and median number of manufacturers (Spearman correlation coefficient, -0.26; P = .005).Conclusions and relevanceThe negative association between the change in drug price and the median number of manufacturers of generic topical dermatologic drugs indicates a role for market competition in controlling the costs of generic drug prices within dermatology. These findings support policies that facilitate robust market competition among topical dermatologic generic drugs produced by a limited number of manufacturers.
| S-EPMC6583314 | biostudies-literature
Project description:Background: Homeopathic Arnica montana is used in surgery as prevention or treatment for the reduction of pain and other sequelae of surgery. Our aim was to perform a metaanalysis of clinical trials to assess efficacy of Arnica montana to reduce the inflammatory response after surgery. Method: We conducted a systematic review and metaanalysis, following a predefined protocol, of all studies on the use of homeopathic Arnica montana in surgery. We included all randomized and nonrandomized studies comparing homeopathic Arnica to a placebo or to another active comparator and calculated two quantitative metaanalyses and appropriate sensitivity analyses. We used "Hegde's g," an effect size estimator which is equivalent to a standardized mean difference corrected for small sample bias. The PROSPERO registration number is CRD42020131300. Results: Twenty-three publications reported on 29 different comparisons. One study had to be excluded because no data could be extracted, leaving 28 comparisons. Eighteen comparisons used placebo, nine comparisons an active control, and in one case Arnica was compared to no treatment. The metaanalysis of the placebo-controlled trials yielded an overall effect size of Hedge's g = 0.18 (95% confidence interval -0.007/0.373; p = 0.059). Active comparator trials yielded a highly heterogeneous significant effect size of g = 0.26. This is mainly due to the large effect size of nonrandomized studies, which converges against zero in the randomized trials. Conclusion: Homeopathic Arnica has a small effect size over and against placebo in preventing excessive hematoma and other sequelae of surgeries. The effect is comparable to that of anti-inflammatory substances.
| S-EPMC8718509 | biostudies-literature
Project description:Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of treatments for rheumatoid arthritis. Unlike randomized controlled trials (RCTs), however, observational studies of drug effects have methodological limitations such as confounding by indication. Active-comparator designs and new-user designs can help mitigate such biases in observational studies and improve the validity of their findings by making them more closely approximate RCTs. In an active-comparator study, the drug of interest is compared with another agent commonly used for the same indication, rather than with no treatment (a 'non-user' group). This principle helps to ensure that treatment groups have similar treatment indications, attenuating both measured and unmeasured differences in patient characteristics. The new-user study includes a cohort of patients from the time of treatment initiation, enabling assessment of patients' pretreatment characteristics and capture of all events occurring during follow-up. These two principles should be considered when designing or reviewing observational studies of drug effects.
| S-EPMC4486631 | biostudies-literature
Project description:BackgroundMedicinal plants have been used traditionally since centuries for wound care and treatment of skin diseases both in human and animals. Skin diseases are one of the most common reasons for owners to take their dog to the veterinarian. The demands for treatment and prophylaxis of these diseases are broad. A wide range of bacteria including antibiotic-resistant bacteria can be involved, making the treatment challenging and bear an anthropo-zoonotic potential. The aim of this review is to systematically evaluate based on recent scientific literature, the potential of four medicinal plants to enrich the therapeutic options in pyoderma, canine atopic dermatitis, otitis externa, wounds and dermatophytosis in dogs.ResultsBased on four books and a survey among veterinarians specialized in phytotherapy, four medicinal plants were chosen as the subject of this systematic review: Calendula officinalis L. (Marigold), Hypericum perforatum L. agg. (St. John's Wort), Matricaria chamomilla L. (syn. Matricaria recutita L., Chamomile) and Salvia officinalis L. (Sage). According to the PRISMA statement through literature research on two online databases a total of 8295 publications was screened and narrowed down to a final 138 publications for which full-text documents were analyzed for its content resulting in a total of 145 references (21 clinical, 24 in vivo and 100 in vitro references).ConclusionsAll four plants were proven to have antibacterial and antifungal effects of a rather broad spectrum including antibiotic-resistant bacteria. This makes them an interesting new option for the treatment of pyoderma, otitis externa, infected wounds and dermatophytosis. Marigold, St. John's Wort and Chamomile showed wound-healing properties and are thus promising candidates in line to fill the therapeutic gap in canine wound-healing agents. St. John's Wort and Chamomile also showed anti-inflammatory and other beneficial effects on healthy skin. Due to the wide range of beneficial effects of these medicinal plants, they should be taken into account for the treatment of dermatologic diseases in dogs at least in future clinical research.
| S-EPMC6537371 | biostudies-literature
Project description:Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the "Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.
| S-EPMC9400320 | biostudies-literature
Project description:Desmetramadol is an investigational analgesic consisting of (+) and (-) enantiomers of the tramadol metabolite O-desmethyltramadol (M1). Tramadol is racemic and exerts analgesia by monoaminergic effects of (-)-tramadol and (-)-M1, and by the opioid (+)-M1. Tramadol labeling indicates cytochrome P450 (CYP) isozyme 2D6 ultrarapid metabolizer can produce dangerous (+)-M1 levels, and CYP2D6 poor metabolizers insufficient (+)-M1 for analgesia. We hypothesized that desmetramadol could provide the safety and analgesia of tramadol without its metabolic liabilities. We conducted consecutive double-blind, randomized, placebo-controlled, 3 segment cross-over trials A and B to investigate the steady-state pharmacokinetics and analgesia of 20 mg desmetramadol and 50 mg tramadol in 103 healthy participants without (n?=?43) and with (n?=?60) cotreatment with the CYP inhibitor paroxetine. In the absence of CYP inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed every 6 hours gave equivalent steady-state (+)-M1, similar adverse events, and analgesia significantly greater than placebo, but equal to each other. In trial B, CYP inhibition significantly depressed tramadol steady-state (+)-M1, reduced its adverse events, and led to insignificant analgesia comparable with placebo. In contrast, CYP inhibition in trial B had no deleterious effect on desmetramadol (+)-M1 or (-)-M1, which gave significant analgesia as in trial A and superior to tramadol (P?=?.003). Desmetramadol has the safety and efficacy of tramadol without its metabolic liabilities. CLINICALTRIALS.GOV REGISTRATIONS: NCT02205554, NCT03312777 PERSPECTIVE: To our knowledge, this is the first study of desmetramadol in humans and the first to show it provides the same safety and analgesia as tramadol, but without tramadol's metabolic liabilities and related drug-drug interactions. Desmetramadol could potentially offer expanded safety and usefulness to clinicians seeking an alternative to schedule II opioids.
| S-EPMC6790288 | biostudies-literature
Project description:Background and aimsThe advent of biologic drugs revolutionised the treatment of many chronic inflammatory diseases in rheumatology, dermatology, and gastroenterology. The introduction of different targeted agents closely followed the increase in knowledge of pathogenic mechanisms. The identification of IL-23 as a master regulator of 'pathogenic' inflammation and the consequent efficacy of IL-23 blocking agents were first proofed in psoriasis and then in other inflammatory diseases such as psoriatic arthritis and Crohn's disease.MethodsWe reviewed all available results from anti-Il-23 clinical trials for psoriasis, focusing on data of IBDologists' interest. Regarding guselkumab, we analysed data from phase III clinical trials VOYAGE1, VOYAGE2, and NAVIGATE. For risankizumab, we reported efficacy and safety results from UltIMMa-1, UltIMMa-2, and IMMvent clinical trials, and tildrakizumab was evaluated by analysing data from reSURFACE1 and reSURFACE2 studies.ResultsData from all the clinical trials that we reported showed both the efficacy of all three anti-IL-23 drugs in psoriasis and the safety of this class; in particular, no gastrointestinal side effects were observed in those studies. IL-23 blockers have shown promising short- and long-term results in psoriasis, with a major safety profile and no negative interactions with gastrointestinal system.ConclusionsAnti-IL-23 indication for psoriatic arthritis is very recent and for IBD is still to come. Therefore, dermatologists are accumulating long-term experience with these drugs, both in clinical trials and in real-world evidence, which can help gastroenterologists in the management of IBD patients.
| S-EPMC9097670 | biostudies-literature
Project description:Botulinum toxin is a superfamily of neurotoxins produced by the bacterium Clostridium Botulinum with well-established efficacy and safety profile in focal idiopathic hyperhidrosis. Recently, botulinum toxins have also been used in many other skin diseases, in off label regimen. The objective of this manuscript is to review and analyze the main therapeutic applications of botulinum toxins in skin diseases. A systematic review of the published data was conducted, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Botulinum toxins present several label and off-label indications of interest for dermatologists. The best-reported evidence concerns focal idiopathic hyperhidrosis, Raynaud phenomenon, suppurative hidradenitis, Hailey-Hailey disease, epidermolysis bullosa simplex Weber-Cockayne type, Darier's disease, pachyonychia congenita, aquagenic keratoderma, alopecia, psoriasis, notalgia paresthetica, facial erythema and flushing, and oily skin. Further clinical trials are still needed to better understand the real efficacy and safety of these applications and to standardize injection and doses protocols for off label applications.
| S-EPMC7915854 | biostudies-literature