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1.
Neurology ; 103(1): e209533, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38833654

RESUMEN

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial ("bypass") or despite a negative phase 2 efficacy result ("override"). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes. METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override. RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65). DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.


Asunto(s)
Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Enfermedades del Sistema Nervioso , Humanos , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/epidemiología , Desarrollo de Medicamentos/métodos , Prevalencia
2.
Stat Med ; 43(19): 3595-3612, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-38881219

RESUMEN

An assurance calculation is a Bayesian alternative to a power calculation. One may be performed to aid the planning of a clinical trial, specifically setting the sample size or to support decisions about whether or not to perform a study. Immuno-oncology is a rapidly evolving area in the development of anticancer drugs. A common phenomenon that arises in trials of such drugs is one of delayed treatment effects, that is, there is a delay in the separation of the survival curves. To calculate assurance for a trial in which a delayed treatment effect is likely to be present, uncertainty about key parameters needs to be considered. If uncertainty is not considered, the number of patients recruited may not be enough to ensure we have adequate statistical power to detect a clinically relevant treatment effect and the risk of an unsuccessful trial is increased. We present a new elicitation technique for when a delayed treatment effect is likely and show how to compute assurance using these elicited prior distributions. We provide an example to illustrate how this can be used in practice and develop open-source software to implement our methods. Our methodology has the potential to improve the success rate and efficiency of Phase III trials in immuno-oncology and for other treatments where a delayed treatment effect is expected to occur.


Asunto(s)
Teorema de Bayes , Proyectos de Investigación , Humanos , Tamaño de la Muestra , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Ensayos Clínicos como Asunto/métodos , Simulación por Computador , Antineoplásicos/uso terapéutico , Factores de Tiempo , Análisis de Supervivencia , Retraso del Tratamiento
4.
Stat Med ; 43(12): 2368-2388, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38564226

RESUMEN

Common statistical theory applicable to confirmatory phase III trial designs usually assumes that patients are enrolled simultaneously and there is no time gap between enrollment and outcome observation. However, in practice, patients are enrolled successively and there is a lag between the enrollment of a patient and the measurement of the primary outcome. For single-stage designs, the difference between theory and practice only impacts on the trial duration but not on the statistical analysis and its interpretation. For designs with interim analyses, however, the number of patients already enrolled into the trial and the number of patients with available outcome measurements differ, which can cause issues regarding the statistical analyses of the data. The main issue is that current methodologies either imply that at the time of the interim analysis there are so-called pipeline patients whose data are not used to make a statistical decision (like stopping early for efficacy) or the enrollment into the trial needs to be at least paused for interim analysis to avoid pipeline patients. There are methods for delayed responses available that introduced error-spending stopping boundaries for the enrollment of patients followed by critical values to reject the null hypothesis in case the stopping boundaries have been crossed beforehand. Here, we will discuss other solutions, considering different boundary determination algorithms using conditional power and introducing a design allowing for recruitment restart while keeping the type I error rate controlled.


Asunto(s)
Ensayos Clínicos Fase III como Asunto , Proyectos de Investigación , Humanos , Ensayos Clínicos Fase III como Asunto/métodos , Modelos Estadísticos , Simulación por Computador , Factores de Tiempo , Interpretación Estadística de Datos , Resultado del Tratamiento , Retraso del Tratamiento
5.
BMC Med Res Methodol ; 24(1): 101, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38689224

RESUMEN

BACKGROUND: Vaccine efficacy (VE) assessed in a randomized controlled clinical trial can be affected by demographic, clinical, and other subject-specific characteristics evaluated as baseline covariates. Understanding the effect of covariates on efficacy is key to decisions by vaccine developers and public health authorities. METHODS: This work evaluates the impact of including correlate of protection (CoP) data in logistic regression on its performance in identifying statistically and clinically significant covariates in settings typical for a vaccine phase 3 trial. The proposed approach uses CoP data and covariate data as predictors of clinical outcome (diseased versus non-diseased) and is compared to logistic regression (without CoP data) to relate vaccination status and covariate data to clinical outcome. RESULTS: Clinical trial simulations, in which the true relationship between CoP data and clinical outcome probability is a sigmoid function, show that use of CoP data increases the positive predictive value for detection of a covariate effect. If the true relationship is characterized by a decreasing convex function, use of CoP data does not substantially change positive or negative predictive value. In either scenario, vaccine efficacy is estimated more precisely (i.e., confidence intervals are narrower) in covariate-defined subgroups if CoP data are used, implying that using CoP data increases the ability to determine clinical significance of baseline covariate effects on efficacy. CONCLUSIONS: This study proposes and evaluates a novel approach for assessing baseline demographic covariates potentially affecting VE. Results show that the proposed approach can sensitively and specifically identify potentially important covariates and provides a method for evaluating their likely clinical significance in terms of predicted impact on vaccine efficacy. It shows further that inclusion of CoP data can enable more precise VE estimation, thus enhancing study power and/or efficiency and providing even better information to support health policy and development decisions.


Asunto(s)
Eficacia de las Vacunas , Humanos , Modelos Logísticos , Eficacia de las Vacunas/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Vacunación/estadística & datos numéricos , Vacunación/métodos , Vacunas/uso terapéutico , Demografía/estadística & datos numéricos , Simulación por Computador , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto/métodos
6.
Contemp Clin Trials ; 141: 107506, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38508234

RESUMEN

BACKGROUND: Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use. METHODS: We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others). RESULTS: A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design. CONCLUSION: The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.


Asunto(s)
Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Humanos , Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados no Aleatorios como Asunto
7.
Pharm Stat ; 23(4): 570-584, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38317373

RESUMEN

In recently conducted phase III trials in a rare disease area, patients received monthly treatment at a high dose of the drug, which targets to lower a specific biomarker level, closely associated with the efficacy endpoint, to around 10% across patients. Although this high dose demonstrated strong efficacy, treatments were withheld due to the reports of serious adverse events. Dosing in these studies were later resumed at a reduced dosage which targets to lower the biomarker level to 15%-35% across patients. Two questions arose after this disruption. The first is whether the efficacy of this revised regimen as measured by the reduction in annualized event rate is adequate to support the continuation of the development and the second is whether the potential bias due to the loss of patients during this dosing gap process can be gauged. To address these questions, we built a prediction model that quantitatively characterizes biomarker vs. endpoint relationship and predicts efficacy at the 15%-35% range of the biomarker level using the available data from the original high dose. This model predicts favorable event rate in the target biomarker level and shows that the bias due to the loss of patients is limited. These results support the continued development of the revised regimen, however, given the limitation of the data available, this prediction is planned to be validated further when data under the revised regimen become available.


Asunto(s)
Biomarcadores , Ensayos Clínicos Fase III como Asunto , Modelos Estadísticos , Humanos , Ensayos Clínicos Fase III como Asunto/métodos , Relación Dosis-Respuesta a Droga , Resultado del Tratamiento
8.
Pharm Stat ; 23(4): 495-510, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38326967

RESUMEN

We present the motivation, experience, and learnings from a data challenge conducted at a large pharmaceutical corporation on the topic of subgroup identification. The data challenge aimed at exploring approaches to subgroup identification for future clinical trials. To mimic a realistic setting, participants had access to 4 Phase III clinical trials to derive a subgroup and predict its treatment effect on a future study not accessible to challenge participants. A total of 30 teams registered for the challenge with around 100 participants, primarily from Biostatistics organization. We outline the motivation for running the challenge, the challenge rules, and logistics. Finally, we present the results of the challenge, the participant feedback as well as the learnings. We also present our view on the implications of the results on exploratory analyses related to treatment effect heterogeneity.


Asunto(s)
Ensayos Clínicos Fase III como Asunto , Motivación , Humanos , Ensayos Clínicos Fase III como Asunto/métodos , Industria Farmacéutica , Proyectos de Investigación , Resultado del Tratamiento , Bioestadística/métodos , Interpretación Estadística de Datos
9.
Clin Trials ; 21(3): 273-286, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38243399

RESUMEN

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.


Asunto(s)
Dosis Máxima Tolerada , Proyectos de Investigación , Humanos , Relación Dosis-Respuesta a Droga , Programas Informáticos , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/métodos , Estados Unidos , United States Food and Drug Administration , Ensayos Clínicos Fase III como Asunto/métodos
10.
PLoS Negl Trop Dis ; 16(1): e0010089, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34990453

RESUMEN

BACKGROUND: Only one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago-the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence. METHODOLOGY: We convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology. RESULTS: A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols. CONCLUSIONS: This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level.


Asunto(s)
Antivirales/farmacología , Ensayos Clínicos Fase III como Asunto/métodos , Desarrollo de Medicamentos/métodos , Fiebre de Lassa/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Humanos , Virus Lassa/efectos de los fármacos , Proyectos de Investigación , Encuestas y Cuestionarios
11.
Expert Opin Investig Drugs ; 31(2): 163-172, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35060815

RESUMEN

INTRODUCTION: Patients with nonalcoholic steatohepatitis (NASH)-associated cirrhosis have the highest rates of major adverse liver outcomes (MALO) within the fatty liver disease spectrum and therefore have the highest unmet need for effective therapeutic agents. Several drugs are being tested for patients with NASH cirrhosis with different mechanisms of action and endpoints. AREAS COVERED: This article summarizes the available data on the natural history of NASH cirrhosis and the rates of developing MALO. We provide examples of ongoing clinical trials for NASH cirrhosis including the study design and endpoints. We then discuss the FDA-guidance on acceptable endpoints for NASH cirrhosis trials that will lead to approval. EXPERT OPINION: Metabolic and antifibrotic drugs are currently in phase 2b trials for NASH cirrhosis with outcomes ranging from histologic improvement on liver biopsy to the development of varices or MALO. We provide the readers with pragmatic advice on trial design for phase 2B and 3 NASH cirrhosis trials. The data presented in the article justify further development and investigation of therapeutic agents for the treatment of NASH cirrhosis.


Asunto(s)
Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Desarrollo de Medicamentos , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Proyectos de Investigación
12.
J Surg Oncol ; 125(1): 34-37, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34897707

RESUMEN

Treatment of regional lymph nodes in melanoma has been controversial for more than a century. A series of clinical trials evaluating elective lymph node dissection and then sentinel lymph node biopsy have helped define the current standard of care. These trials resulted in increasingly selective application of surgical intervention for regional lymph nodes in melanoma. First by focusing on optimal candidates for elective lymph node dissection and then by identifying patients through sentinel lymph node biopsy. The current standard of sentinel lymph node biopsy for appropriately selected patients and nodal observation for many patients, even with involved sentinel nodes is both more accurate in staging and much less morbid than what came before.


Asunto(s)
Ensayos Clínicos como Asunto/métodos , Ganglios Linfáticos/cirugía , Melanoma/cirugía , Ensayos Clínicos como Asunto/historia , Ensayos Clínicos Fase III como Asunto/historia , Ensayos Clínicos Fase III como Asunto/métodos , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática , Melanoma/historia , Melanoma/patología , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto/historia , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Biopsia del Ganglio Linfático Centinela/métodos
13.
J Surg Oncol ; 125(1): 17-27, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34897708

RESUMEN

Soft-tissue sarcomas are rare tumors arising from mesenchymal tissues. As a heterogeneous group comprising more than 50 types, the development of clinical trials remains challenging. Decision-making for neoadjuvant or adjuvant chemotherapy and radiation therapy is based on the available evidence of contemporary trials and multidisciplinary clinical judgment.


Asunto(s)
Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Quimioterapia Adyuvante , Humanos , Terapia Neoadyuvante , Radioterapia Adyuvante , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos
14.
Cancer Treat Rev ; 102: 102321, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34852292

RESUMEN

Health-related quality of life (HRQOL) is increasingly recognized as important when evaluating cancer treatments. The use, reporting, and analysis of patient-reported outcome measures (PROMs), however, are not standardized in clinical trials and are often poorly implemented in clinical practice. We report the results of a systematic literature review (PubMed search: January 1, 2000 to August 15, 2020) of PROM use, reporting, and analysis in phase 3 clinical trials of hormone receptor-positive (HR+) advanced breast cancer (ABC). Further inspection of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor publications was performed to examine PROMs in the HR+/human epidermal growth factor receptor 2-negative setting. A total of 88 results were identified in the initial search; 32 were included in the final analysis. Among included studies, most (66%) had been published in the last 5 years (2015 to 2020). CDK4/6 inhibitors (38%) were the most common agents reported. No clear standard for PROM use, reporting, or analysis was found. The most common PROMs were European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 59%) and the Functional Assessment of Cancer Therapy-Breast (FACT-B; 34%). Important differences, among studies that reported them, ranged from 5 to 10 points for the EORTC QLQ-C30 and 8 points for the FACT-B total score. This review showed that a lack of clear consistency remains for PROM use, reporting, and analysis in phase 3 clinical trials of HR+ ABC. However, HRQOL is of high interest in the literature, including for CDK4/6 inhibitors.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Neoplasias de la Mama/metabolismo , Ensayos Clínicos Fase III como Asunto/métodos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Humanos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Receptores de Esteroides/metabolismo
16.
J Neuroinflammation ; 18(1): 208, 2021 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-34530847

RESUMEN

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19+ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Autoanticuerpos/metabolismo , Inmunosupresores/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Acuaporina 4/inmunología , Acuaporina 4/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Astrocitos/metabolismo , Autoanticuerpos/efectos de los fármacos , Autoanticuerpos/inmunología , Azatioprina/farmacología , Azatioprina/uso terapéutico , Ensayos Clínicos Fase III como Asunto/métodos , Humanos , Inmunosupresores/farmacología , Neuromielitis Óptica/inmunología
17.
CNS Drugs ; 35(10): 1069-1079, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34491545

RESUMEN

Nearly 5% of individuals in the USA had serious thoughts of suicide in 2019 and over 30% of individuals suffering with major depressive disorder reported suicidal ideation with 2 million of those reporting suicidal ideation with some level of intent. However, options to treat depressed individuals considered at imminent risk of suicide remain limited. Until the recent approval of esketamine in the treatment of patients with major depressive disorder with serious suicidal thoughts or actions, no medications had been specifically evaluated for use in this population in the acute setting. This review discusses the history and the current understanding of the role of ketamine and esketamine in depression and suicidal ideation and behavior. It covers some of the pivotal studies in this field and provides a summary of their major findings. The trials of esketamine in patients with major depressive disorder with active suicidal ideation or behavior are the first large-scale trials in patients considered at imminent risk of suicide. As such, the design of these studies is by definition novel, a fact that complicates the interpretation of the data and assessment of the true clinical meaningfulness of the findings. Despite this, the findings in toto draw a consistent picture of benefits that appears to outweigh the potential risks of the treatment. The studies also serve to highlight the complexities and limitations associated with clinical trials aiming to test the ability of novel therapeutics to reduce the burden and risks in patients with suicide ideation and behavior.


Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Manejo de la Enfermedad , Ketamina/uso terapéutico , Ideación Suicida , Ensayos Clínicos Fase III como Asunto/métodos , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Humanos , Medición de Riesgo/métodos
18.
J Neuroendocrinol ; 33(9): e13015, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34397130

RESUMEN

The quality and reporting of neuroendocrine tumour (NET) clinical trials has previously been found to be heterogeneous impairing trial interpretability. We aimed to perform an updated review of the quality of phase II/III clinical trials in NET to assess if trial design and reporting have improved since 2011. We performed a PubMed search for phase II/III trials evaluating systemic anticancer therapies or liver-directed therapies published between 2011 and 2018. Data collected comprised administrative data, study population characteristics, endpoints, reporting and statistical design parameters, and results. Sixty studies were included (5218 patients): 50 phase II and 10 phase III trials. Study populations were heterogeneous: 52% of trials allowed tumours from various primary sites, 28% allowed both well- and poorly-differentiated tumour morphology or did not specify, and 57% did not report proliferative indices and/or tumour grade in ≥80% of the study population. Only 36% of trials mandated radiological disease progression on participant enrolment using a validated measure. Statistical design and primary endpoint were clearly defined in 67% and 88% of trials, respectively. Toxicity (88%), radiological response rate (85%) and progression-free survival/time to progression (82%) were well reported in a majority of trials, but health-related quality of life was included in the minority. Of the randomised trials (n = 11), study populations were more homogeneous and study design was more often clearly defined; however, only 45% mandated radiological progression at baseline as measured per Response Evaluation Criteria In Solid Tumours, and reporting of health-related quality of life (55%) remained suboptimal. The design and reporting of NET clinical trials, predominantly of single-arm phase II trials, remains suboptimal and has not considerably improved over time despite the growth in our knowledge of the biology and unique characteristics of NETs. Higher quality is seen in randomised trials, although certain design and reporting elements remain inadequate in some studies. We must prioritise the design and conduct of NET clinical trials to effectively inform future research and guide practice change.


Asunto(s)
Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Tumores Neuroendocrinos/tratamiento farmacológico , Reportes Públicos de Datos en Atención de Salud , Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/normas , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/normas , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Exactitud de los Datos , Humanos , Tumores Neuroendocrinos/epidemiología , Proyectos de Investigación/normas
20.
Respir Res ; 22(1): 184, 2021 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-34158028

RESUMEN

BACKGROUND: Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma. METHODS: This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (< 18 years; 18-40 years; ≥ 40 years); lung function (% predicted FEV1 ≤ 60; 60-80; > 80); airway reversibility (reversible [≥ 12% change in FEV1]; non-reversible [< 12% change in FEV1]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score < 1.5]). RESULTS: Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49-63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons. CONCLUSIONS: Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto/métodos , Volumen Espiratorio Forzado/fisiología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Asma/diagnóstico , Asma/fisiopatología , Progresión de la Enfermedad , Humanos , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad
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