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Journal of Pharmacokinetics and... Jun 2022Exposure-response modeling is important to optimize dose and dosing regimens in clinical drug development. While primary clinical trial endpoints often have few...
Exposure-response modeling is important to optimize dose and dosing regimens in clinical drug development. While primary clinical trial endpoints often have few categories and thus provide only limited information, sometimes there may be additional, more informative endpoints. Benefits of fully incorporating relevant information in longitudinal exposure-response modeling through joint modeling have recently been shown. This manuscript aims to further investigate the benefit of joint modeling of an ordered categorical primary endpoint with a related near-continuous endpoint, through the sharing of model parameters in the latent variable indirect response (IDR) modeling framework. This is illustrated by analyzing the data collected through up to 116 weeks from a phase 3b response-adaptive trial of ustekinumab in patients with psoriasis. The primary endpoint was based on the 6-point physician's global assessment (PGA) score. The Psoriasis area and severity Index (PASI) data, ranging from 0 to 72 with 0.1 increments, were also available. Separate and joint latent variable Type I IDR models of PGA and PASI scores were developed and compared. The results showed that the separate PGA model had a substantial structural bias, which was corrected by the joint modeling of PGA and PASI scores.
Topics: Humans; Double-Blind Method; Psoriasis; Severity of Illness Index; Treatment Outcome; Ustekinumab
PubMed: 34800232
DOI: 10.1007/s10928-021-09796-3 -
Vaccine Aug 2019Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure... (Review)
Review
Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure and pre-qualification. To that end, the field of vaccine development for Shigella, enterotoxigenic Escherichia coli (ETEC) as well as other enteric pathogens would benefit greatly from a focused review of clinical endpoints and the use of common endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. A workshop was conducted to review clinical endpoints from controlled human challenge studies, field studies in naïve adult travelers and pediatric studies in low-middle income countries and to develop a consensus on clinical endpoints for future vaccine trials. Following sequential presentations on different study designs (CHIM, travelers' efficacy and pediatric efficacy), workshop participants broke into three simultaneous workgroups focused on those study designs to discuss a number of topics key to clinical endpoints specific to each study design. Previously utilized endpoints were reviewed with an eye towards potentially novel endpoints for future studies and consideration of the disease parameters and spectrum of disease targeted for prevention. The strength of support among workshop participants for the use of various endpoints is summarized as are recommendations for additional endpoints to be considered in future studies. It is anticipated that this report will facilitate endpoint determination in future efficacy trials of vaccine candidates.
Topics: Adult; Child, Preschool; Clinical Trials as Topic; Congresses as Topic; Developing Countries; Diarrhea; Dysentery, Bacillary; Endpoint Determination; Enterotoxigenic Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Humans; Immunization; Immunogenicity, Vaccine; Models, Immunological; Shigella; Shigella Vaccines; Travel
PubMed: 30981626
DOI: 10.1016/j.vaccine.2019.03.051 -
Anti-cancer Drugs Oct 2014The aim of this study was to analyse trial variables affecting drug approval in metastatic breast cancer (MBC). A literature search from 2000 to 2012 retrieved 66 phase... (Review)
Review
The aim of this study was to analyse trial variables affecting drug approval in metastatic breast cancer (MBC). A literature search from 2000 to 2012 retrieved 66 phase III randomized controlled trials with reported primary endpoints in MBC and known outcomes in terms of approval. The influence of the primary endpoint, the line of therapy, crossover and the sample size was analysed. The primary endpoints used most frequently were progression-free survival (PFS) and time to progression or time to treatment failure (N=47; 71%). Overall survival (OS) was a primary endpoint in nine trials (14%). In 26 trials (39%), statistically significant results were found with respect to the primary endpoint, and in 13 trials (20%), this was found with respect to the secondary endpoint. Gains in OS were found in 12 trials (18%), whereas a benefit to PFS was found in 30 trials (46%). The average median OS was 23.1 months. Postprogression survival accounted for 64% of OS. Trials with crossover did not have OS as the primary endpoint. Trials that resulted in drug approval had a more pronounced gain in OS or PFS and had more patients than those without regulatory consequences. PFS was the main primary endpoint in randomized clinical trials in MBC and was significantly associated with drug approval. OS benefit was rarely achieved in trials where this was not the primary endpoint. The number of randomized patients, the primary endpoint and crossover are factors linked to regulatory requirements for approval, which should be considered in future trial designs.
Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Drug Approval; Female; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Treatment Failure
PubMed: 24892723
DOI: 10.1097/CAD.0000000000000130 -
Statistics in Medicine Jul 2016When efficacy of a treatment is measured by co-primary endpoints, efficacy is claimed only if for each endpoint an individual statistical test is significant at level...
When efficacy of a treatment is measured by co-primary endpoints, efficacy is claimed only if for each endpoint an individual statistical test is significant at level α. While such a strategy controls the family-wise type I error rate (FWER), it is often strictly conservative and allows for no inference if not all null hypotheses can be rejected. In this paper, we investigate fallback tests, which are defined as uniform improvements of the classical test for co-primary endpoints. They reject whenever the classical test rejects but allow for inference also in settings where only a subset of endpoints show a significant effect. Similarly to the fallback tests for hierarchical testing procedures, these fallback tests for co-primary endpoints allow one to continue testing even if the primary objective of the trial was not met. We propose examples of fallback tests for two and three co-primary endpoints that control the FWER in the strong sense under the assumption of multivariate normal test statistics with arbitrary correlation matrix and investigate their power in a simulation study. The fallback procedures for co-primary endpoints are illustrated with a clinical trial in a rare disease and a diagnostic trial. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.
Topics: Biometry; Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans
PubMed: 26919166
DOI: 10.1002/sim.6911 -
European Heart Journal Apr 2008The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione.... (Meta-Analysis)
Meta-Analysis Review
The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione. It has provided valuable information on the impact of pioglitazone on CV outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. The investigators in PROactive chose a challenging primary composite endpoint that included events in multiple vascular beds (cerebral, cardiac, and peripheral), as well as both disease-related and procedural endpoints. They also pre-specified a more conventional main secondary composite endpoint of all-cause mortality, myocardial infarction, and stroke. Since the results of PROactive were first presented, there has been much debate on the relative merits of the statistically non-significant 10% decrease in the primary endpoint vs. the statistically significant 16% decrease in the main secondary endpoint seen with pioglitazone. However, PROactive includes more information than just these two main endpoints and has provided an extensive safety data set, as well as new insights into the impact of pioglitazone in different patient subpopulations. In this article, we consider all the results from PROactive presented to date and offer our own appraisal of how these findings shape the CV efficacy and safety profile of pioglitazone.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Pioglitazone; Randomized Controlled Trials as Topic; Thiazolidinediones; Treatment Outcome
PubMed: 18375395
DOI: 10.1093/eurheartj/ehn114 -
HPB : the Official Journal of the... Nov 2017Adjuvant chemotherapy (CT) is the standard of care for patients with resected pancreatic cancer (PC). Overall survival (OS) has traditionally represented the primary... (Review)
Review
BACKGROUND
Adjuvant chemotherapy (CT) is the standard of care for patients with resected pancreatic cancer (PC). Overall survival (OS) has traditionally represented the primary endpoint in randomized trials assessing adjuvant therapies for PC. The aim of this study was to assess if disease-free survival (DFS) was an adequate surrogate endpoint for OS in randomized trials of adjuvant therapy in PC.
METHODS
A systematic literature search was conducted in PubMed, Web of Science, SCOPUS and Embase, Cochrane Library and the World Health Organization International Clinical Trials Registry Platform up to February 2nd, 2017. Surrogacy of DFS with OS was assessed between endpoints and OS through the Spearman rank correlation coefficient, and between the treatment effects on the endpoints using the squared correlation R.
RESULTS
A total of 12 eligible randomized trials that enrolled 4,888 patients where identified for the final analysis. Correlation of DFS with OS was weak at the individual level (Spearman rank correlation coefficient = 0.31) and moderate at the trial level (R = 0.44).
CONCLUSIONS
DFS does not represent an appropriate surrogate for OS in randomized trials of adjuvant therapy for resected PC. Hence, OS should remain the primary endpoint of future trials evaluating new agents in postsurgical setting.
Topics: Chemotherapy, Adjuvant; Disease-Free Survival; Endpoint Determination; Humans; Pancreatectomy; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 28764887
DOI: 10.1016/j.hpb.2017.07.005 -
Leukemia Research May 2018Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many... (Review)
Review
Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial's statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Remission Induction; Treatment Outcome
PubMed: 29524739
DOI: 10.1016/j.leukres.2018.02.002 -
Contemporary Clinical Trials Dec 2022Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who require hospitalization. The Hospital Recovery Scale is an ordinal endpoint used to evaluate treatment outcomes in clinical studies of hospitalized patients infected with influenza.
METHODS
To determine whether Hospital Recovery Scale outcomes correspond to those for other clinical endpoints in patients hospitalized due to influenza, data from the phase 3 randomized, double-blind ZORO clinical trial (NCT01231620) were analyzed. Randomized influenza-infected patients were divided into subgroups of interest based on prespecified baseline and infection-related characteristics, as well as randomized treatment arms (intravenous zanamivir 300 mg or 600 mg, or oral oseltamivir 75 mg). Clinical endpoints relevant to this population were included to analyze differences in outcomes between the subgroups, and correspondence of these endpoints and hospital recovery endpoint was evaluated.
RESULTS
Data from 488 patients were analyzed. There were strong correlations (ρ > 0.8) between the Hospital Recovery Scale assessed on the day after completion of a 5-day antiviral therapy (Day 6) and both time to hospital discharge and time to intensive care unit discharge, and moderate to strong correlations (0.6 < ρ < 0.8) between the Hospital Recovery Scale on Day 6 and several other relevant clinical endpoints.
CONCLUSIONS
The Hospital Recovery Scale is applicable as a primary endpoint in trials to evaluate new therapies for severely ill patients hospitalized due to influenza, and may have utility in other severe respiratory illnesses such as COVID-19.
Topics: Humans; Influenza, Human; COVID-19; Oseltamivir; Hospitalization; Treatment Outcome; Hospitals; Antiviral Agents
PubMed: 36202198
DOI: 10.1016/j.cct.2022.106952 -
CNS Drugs Oct 2009Iloperidone is an atypical antipsychotic that is approved for the treatment of adult patients with schizophrenia. In several large (n > 570 per trial), 4- or 6-week,... (Review)
Review
Iloperidone is an atypical antipsychotic that is approved for the treatment of adult patients with schizophrenia. In several large (n > 570 per trial), 4- or 6-week, double-blind, multinational, multicentre trials in adult patients with schizophrenia, recommended target dosages of oral iloperidone (6-12 mg twice daily) generally showed better efficacy than placebo, in terms of improvements in Positive and Negative Syndrome Scale (PANSS) total scores or Brief Psychiatric Rating Scale (BPRS) scores (primary endpoints) and also for most secondary endpoints, including PANSS subscale scores. In addition, pharmacogenomic studies identified single nucleotide polymorphisms (SNPs) that were associated with an enhanced response to iloperidone during acute treatment of schizophrenia. More limited data also support the role of these SNPs in enhancing responses to iloperidone during longer-term treatment. In a pooled analysis of three 52-week, double-blind, multinational, multicentre trials (n = 473), iloperidone treatment was shown to be equivalent to that with haloperidol, based on Kaplan-Meier estimates of the time to relapse (primary endpoint). Iloperidone was generally well tolerated and was associated with few extrapyramidal symptoms or changes in metabolic parameters in short- and longer-term clinical trials in adult patients with schizophrenia.
Topics: Humans; Internationality; Isoxazoles; Multicenter Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology
PubMed: 19739696
DOI: 10.2165/10489070-000000000-00000 -
The Western Journal of Emergency... Jul 2018Clinicians, institutions, healthcare networks, and policymakers use outcomes reported in clinical trials as the basis for medical decision-making when managing... (Review)
Review
Clinicians, institutions, healthcare networks, and policymakers use outcomes reported in clinical trials as the basis for medical decision-making when managing individual patients or populations. Therefore, the choice of a valid primary endpoint is crucial for randomized controlled trials (RCT) to demonstrate efficacy of new therapies. Recent improvements in treatment, however, have led to a decline in the morbidity and mortality of several common diseases, resulting in a reduction in relevant outcomes that can be used as clinical trial endpoints. Composite endpoints have been used as a solution to maintain the feasibility of RCTs, particularly when facing low event rates, high cost, and long follow-up. However, the benefits of using composite endpoints must be weighed against the risks of misinterpretation by clinicians and policymakers, as incorrect interpretation may have a detrimental effect on patients and populations. This paper defines a composite endpoint, discusses the rationale for its use, and provides a practical approach to interpreting results to aid in medical decision-making.
Topics: Decision Making; Drug Therapy; Endpoint Determination; Humans; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 30013696
DOI: 10.5811/westjem.2018.4.38383